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186 KiB

Open AccessArticle

Polymorphisms in DNA Repair Genes and Susceptibility to Glioma in a Chinese Population

by Wei-Ran Pan, Gang Li and Jun-Hong Guan

Int. J. Mol. Sci. 2013, 14(2), 3314-3324; https://doi.org/10.3390/ijms14023314 - 5 Feb 2013

Cited by 36 | Viewed by 6691

Abstract

The excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1), and X-ray repair cross-complementing group 1 (XRCC1) genes appear to protect mammalian cells from the harmful effects of ionizing radiation. We conducted a large case-control study to investigate the association of polymorphisms [...] Read more.

The excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1), and X-ray repair cross-complementing group 1 (XRCC1) genes appear to protect mammalian cells from the harmful effects of ionizing radiation. We conducted a large case-control study to investigate the association of polymorphisms in ERCC1 C118T, ERCC1 C8092A, XRCC1 A194T, XRCC1 A194T, and XRCC3 C241T, with glioma risk in a Chinese population. Five single nucleotide polymorphisms (SNPs) were genotyped, using the MassARRAY IPLEX platform, in 443 glioma cases and 443 controls. Association analyses based on an χ² test and binary logistic regression were performed to determine the odds ratio (OR) and a 95% confidence interval (95% CI) for each SNP. For XRCC1 Arg194Trp, the variant genotype T/T was strongly associated with a lower risk of glioma cancer when compared with the wild type C/C (OR = 2.45, 95% CI = 1.43–4.45). Individuals carrying the XRCC1 399A allele had an increased risk of glioma (OR = 1.33, 95% CI = 1.02–1.64). The XRCC3 241T/T genotype was associated with a strong increased glioma risk (OR = 3.78, 95% CI = 1.86–9.06). Further analysis of the interactions of two susceptibility-associated SNPs, XRCC1 Arg194Trp and XRCC3 Thr241Met, showed that the combination of the XRCC1 194T and XRCC3 241T alleles brought a large increase in glioma risk (OR = 2.75, 95% CI = 1.54–4.04). XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XRCC3 C241T, appear to be associated with susceptibility to glioma in a Chinese population. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

Anticancer Effects of Bufalin on Human Hepatocellular Carcinoma HepG2 Cells: Roles of Apoptosis and Autophagy

by Qing Miao, Lin-Lin Bi, Xin Li, Shan Miao, Jin Zhang, Song Zhang, Qian Yang, Yan-Hua Xie, Jian Zhang and Si-Wang Wang

Int. J. Mol. Sci. 2013, 14(1), 1370-1382; https://doi.org/10.3390/ijms14011370 - 11 Jan 2013

Cited by 84 | Viewed by 14203

Abstract

The traditional Chinese medicine bufalin, extracted from toad’s skin, has been demonstrated to exert anticancer activities in various kinds of human cancers. The mechanisms of action lie in its capacity to induce apoptosis, or termed type I programmed cell death (PCD). However, type [...] Read more.

The traditional Chinese medicine bufalin, extracted from toad’s skin, has been demonstrated to exert anticancer activities in various kinds of human cancers. The mechanisms of action lie in its capacity to induce apoptosis, or termed type I programmed cell death (PCD). However, type II PCD, or autophagy, participates in cancer proliferation, progression, and relapse, as well. Recent studies on autophagy seem to be controversial because of the dual roles of autophagy in cancer survival and death. In good agreement with previous studies, we found that 100 nM bufalin induced extensive HepG2 cell apoptosis. However, we also noticed bufalin triggered autophagy and enhanced Beclin-1 expression, LC3-I to LC3-II conversion, as well as decreased p62 expression and mTOR signaling activation in HepG2 cells. Blockage of autophagy by selective inhibitor 3-MA decreased apoptotic ratio in bufalin-treated HepG2 cells, suggesting a proapoptotic role of bufalin-induced autophagy. Furthermore, we investigated the underlying mechanisms of bufalin-induced autophagy. Bufalin treatment dose-dependently promoted AMPK phosphorylation while AMPK inhibition by compound C significantly attenuated bufalin-induced autophagy. Taken together, we report for the first time that bufalin induces HepG2 cells PCD, especially for autophagy, and the mechanism of action is, at least in part, AMPK-mTOR dependent. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

Modulation of MDR1 and MRP3 Gene Expression in Lung Cancer Cells after Paclitaxel and Carboplatin Exposure

by Consolación Melguizo, Jose Prados, Raquel Luque, Raúl Ortiz, Octavio Caba, Pablo J. Álvarez, Beatriz Gonzalez and Antonia Aranega

Int. J. Mol. Sci. 2012, 13(12), 16624-16635; https://doi.org/10.3390/ijms131216624 - 5 Dec 2012

Cited by 21 | Viewed by 7458

Abstract

Carboplatin-paclitaxel is a reference regimen in the treatment of locally advanced or disseminated non-small cell lung cancer (NSCLC). This paper discusses the multidrug resistance developed with this drug combination, which is one of the major obstacles to successful treatment. In order to understand [...] Read more.

Carboplatin-paclitaxel is a reference regimen in the treatment of locally advanced or disseminated non-small cell lung cancer (NSCLC). This paper discusses the multidrug resistance developed with this drug combination, which is one of the major obstacles to successful treatment. In order to understand and overcome the drug resistance pattern of NSCLC after carboplatin plus paclitaxel exposure, levels of mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance-associated protein 3 (MRP3) were investigated in primary NSCLC cell lines (A-549 and A-427) and a metastasis-derived NSCLC cell line (NODO). Our results showed that exposure of the three NSCLC lines to plasma concentrations of paclitaxel (5 μM) produced an increase in MDR1 expression, while MRP3 showed no alteration in expression. By contrast, the same cells exposed to carboplatin plasma concentrations (30 μM) showed overexpression of MRP3. In these cells, MDR1 showed no expression changes. Interestingly, the combination of both paclitaxel and carboplatin caused increased expression of the MDR1 drug resistance gene rather than the individual treatments. These results suggest that carboplatin and paclitaxel may induce drug resistance mediated by MDR1 and MRP3, which may be enhanced by the simultaneous use of both drugs. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

Targeting Death Receptor TRAIL-R2 by Chalcones for TRAIL-Induced Apoptosis in Cancer Cells

by Ewelina Szliszka, Dagmara Jaworska, Małgorzata Ksek, Zenon P. Czuba and Wojciech Król

Int. J. Mol. Sci. 2012, 13(11), 15343-15359; https://doi.org/10.3390/ijms131115343 - 20 Nov 2012

Cited by 58 | Viewed by 8481

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells without toxicity to normal cells. TRAIL binds to death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) expressed on cancer cell surface and activates apoptotic pathways. Endogenous TRAIL plays an important role in immune [...] Read more.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells without toxicity to normal cells. TRAIL binds to death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) expressed on cancer cell surface and activates apoptotic pathways. Endogenous TRAIL plays an important role in immune surveillance and defense against cancer cells. However, as more tumor cells are reported to be resistant to TRAIL mediated death, it is important to search for and develop new strategies to overcome this resistance. Chalcones can sensitize cancer cells to TRAIL-induced apoptosis. We examined the cytotoxic and apoptotic effects of TRAIL in combination with four chalcones: chalcone, isobavachalcone, licochalcone A and xanthohumol on HeLa cancer cells. The cytotoxicity was measured by MTT and LDH assays. The apoptosis was detected using annexin V-FITC staining by flow cytometry and fluorescence microscopy. Death receptor expression was analyzed using flow cytometry. The decreased expression of death receptors in cancer cells may be the cause of TRAIL-resistance. Chalcones enhance TRAIL-induced apoptosis in HeLa cells through increased expression of TRAIL-R2. Our study has indicated that chalcones augment the antitumor activity of TRAIL and confirm their cancer chemopreventive properties. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

Genomic Polymorphism of Human Papillomavirus Type 52 in Women from Northeast China

by Zhengrong Sun, Zhitao Lu, Jianhua Liu, Guili Wang, Weiqiang Zhou, Lianxia Yang, Chao Liu and Qiang Ruan

Int. J. Mol. Sci. 2012, 13(11), 14962-14972; https://doi.org/10.3390/ijms131114962 - 15 Nov 2012

Cited by 12 | Viewed by 5768

Abstract

Human papillomavirus (HPV) 52 is an oncogenic HPV type prevalent in Asia. The aim of the study was to analyze HPV 52 genetic variations in women from Northeast China. To explore the intratypic variants of HPV 52, the genomic regions of L1, [...] Read more.

Human papillomavirus (HPV) 52 is an oncogenic HPV type prevalent in Asia. The aim of the study was to analyze HPV 52 genetic variations in women from Northeast China. To explore the intratypic variants of HPV 52, the genomic regions of L1, E6, E7 and long control region (LCR) of HPV 52, which have been identified in women from Northeast China by HPV GenoArray test, were analyzed. Twenty-five mutations were identified in the regions examined. Of the mutations found in the L1 gene, three novel nonsynonymous mutations of C5640T, A5641T and G5642A were located within the region that encodes the binding domain of neutralizing antibodies against HPV 52. Although four variations were identified in HPV 52 E6 and E7 genes, no significant association was found between the mutations and the cytological lesion of the patients. Eight mutations, including a novel CTT7681–7683 deletion, found in the LCR of HPV 52 encompassed the known transcription binding sites, which may possibly affect the transcription of the oncogenic genes of E6 and E7. The most prevalent HPV 52 variant in women from northeastern China belongs to clade L1-LN-A. The genetic variations of HPV 52, including three novel nonsynonymous mutations of C5640T, A5641T and G5642A in the L1 gene and a novel CTT7681–7683 deletion in the LCR, were first documented in strains from women in Northeast China. The statistical result showed no associations between the variants and the severities of the infected women. These findings provide new data regarding gene variations of HPV 52. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

Role of Btg2 in the Progression of a PDGF-Induced Oligodendroglioma Model

by Irene Appolloni, Sebastiano Curreli, Sara Caviglia, Manuela Barilari, Eleonora Gambini, Aldo Pagano and Paolo Malatesta

Int. J. Mol. Sci. 2012, 13(11), 14667-14678; https://doi.org/10.3390/ijms131114667 - 12 Nov 2012

Cited by 8 | Viewed by 6327

Abstract

Tumor progression is a key aspect in oncology. Not even the overexpression of a powerful oncogenic stimulus such as platelet derived growth factor-B (PDGF-B) is sufficient per se to confer full malignancy to cells. In previous studies we showed that neural progenitors overexpressing [...] Read more.

Tumor progression is a key aspect in oncology. Not even the overexpression of a powerful oncogenic stimulus such as platelet derived growth factor-B (PDGF-B) is sufficient per se to confer full malignancy to cells. In previous studies we showed that neural progenitors overexpressing PDGF-B need to undergo progression to acquire the capability to give rise to secondary tumor following transplant. By comparing the expression profile of PDGF-expressing cells before and after progression, we found that progressed tumors consistently downregulate the expression of the antiproliferative gene Btg2. We therefore tested whether the downregulation of Btg2 is sufficient and necessary for glioma progression with loss and gain of function experiments. Our results show that downregulation of Btg2 is not sufficient but is necessary for tumor progression since the re-introduction of Btg2 in fully progressed tumors dramatically impairs their gliomagenic potential. These results suggest an important role of Btg2 in glioma progression. Accordingly with this view, the analysis of public datasets of human gliomas showed that reduced level of Btg2 expression correlates with a significantly worse prognosis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

Protein Profiling of Blood Samples from Patients with Hereditary Leiomyomatosis and Renal Cell Cancer by Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry

by Takao Kamai, Naohisa Tomosugi, Hideyuki Abe, Yasushi Kaji, Tetsunari Oyama and Ken-Ichiro Yoshida

Int. J. Mol. Sci. 2012, 13(11), 14518-14532; https://doi.org/10.3390/ijms131114518 - 8 Nov 2012

Cited by 10 | Viewed by 6849

Abstract

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an extremely rare syndrome with autosomal dominant inheritance. HLRCC is characterized by a predisposition to leiomyomas of the skin and the uterus as well as renal cell carcinoma. The disease-related gene has been identified as [...] Read more.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an extremely rare syndrome with autosomal dominant inheritance. HLRCC is characterized by a predisposition to leiomyomas of the skin and the uterus as well as renal cell carcinoma. The disease-related gene has been identified as fumarate hydratase (fumarase, FH), which encodes an enzyme involved in the mitochondrial tricarboxylic acid cycle. Protein profiling may give some insight into the molecular pathways of HLRCC. Therefore, we performed protein profiling of blood samples from HLRCC patients, their family members, and healthy volunteers, using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) coupled with IMAC-Cu chips. For hierarchical clustering analysis, we used the 45 peaks that revealed significant differences in single-marker analysis over the range from 1500 to 15,000 m/z. Heat map analysis based on the results of clustering distinguished the HLRCC kindred from non-HLRCC subjects with a sensitivity of 94% and a specificity of 90%. SELDI-TOF MS profiling of blood samples can be applied to identify patients with HLRCC and to assess specific molecular mechanisms involved in this condition. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

Quantum Dots-Based Immunofluorescent Imaging of Stromal Fibroblasts Caveolin-1 and Light Chain 3B Expression and Identification of Their Clinical Significance in Human Gastric Cancer

by Yuyu He, Xianda Zhao, Jun Gao, Lifang Fan, Guifang Yang, William Chi-shing Cho and Honglei Chen

Int. J. Mol. Sci. 2012, 13(11), 13764-13780; https://doi.org/10.3390/ijms131113764 - 24 Oct 2012

Cited by 31 | Viewed by 7681

Abstract

Caveolin-1 (Cav-1) expression deficiency and autophagy in tumor stromal fibroblasts (hereafter fibroblasts) are involved in tumor proliferation and progression, particularly in breast and prostate cancer. The aim of this study was to detect the expression of fibroblastic Cav-1 and LC3B, markers of autophagy, [...] Read more.

Caveolin-1 (Cav-1) expression deficiency and autophagy in tumor stromal fibroblasts (hereafter fibroblasts) are involved in tumor proliferation and progression, particularly in breast and prostate cancer. The aim of this study was to detect the expression of fibroblastic Cav-1 and LC3B, markers of autophagy, in gastric cancer (GC) and to analyze their clinical significances. Furthermore, because Epstein-Barr virus (EBV)-associated GC (EBVaGC) is a unique subtype of GC; we compared the differential expression of fibroblastic Cav-1 and LC3B in EBVaGC and non-EBVaGC. Quantum dots (QDs)-based immunofluorescence histochemistry was used to examine the expression of fibroblastic Cav-1 and LC3B in 118 cases of GC with adequate stroma. QDs-based double immunofluorescence labeling was performed to detect the coexpression of Cav-1 and LC3B proteins. EBV-encoded small RNA was detected by QDs-based fluorescence in situ hybridization to identify EBVaGC. Multivariate analysis indicated that low fibroblastic Cav-1 level was an independent prognosticator (p = 0.029) that predicted poorer survival of GC patients. Positive fibroblastic LC3B was correlated with lower invasion (p = 0.032) and was positively associated with Cav-1 expression (r = 0.432, p < 0.001). EBV infection did not affect fibroblastic Cav-1 and LC3B expression. In conclusion, positive fibroblastic LC3B correlates with lower invasion, and low expression of fibroblastic Cav-1 is a novel predictor of poor GC prognosis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

Altered DNA Binding and Amplification of Human Breast Cancer Suppressor Gene BRCA1 Induced by a Novel Antitumor Compound, [Ru(η⁶-p-phenylethacrynate)Cl₂(pta)]

by Korawan Chakree, Chitchamai Ovatlarnporn, Paul J. Dyson and Adisorn Ratanaphan

Int. J. Mol. Sci. 2012, 13(10), 13183-13202; https://doi.org/10.3390/ijms131013183 - 15 Oct 2012

Cited by 21 | Viewed by 9163

Abstract

The ruthenium-based complex [Ru(η⁶-p-phenylethacrynate)Cl₂(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane), termed ethaRAPTA, is an interesting antitumor compound. The elucidation of the molecular mechanism of drug activity is central to the drug development program. To this end, we have characterized the [...] Read more.

The ruthenium-based complex [Ru(η⁶-p-phenylethacrynate)Cl₂(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane), termed ethaRAPTA, is an interesting antitumor compound. The elucidation of the molecular mechanism of drug activity is central to the drug development program. To this end, we have characterized the ethaRAPTA interaction with DNA, including probing the sequence specific modified DNA structural stability and DNA amplification using the breast cancer suppressor gene 1 (BRCA1) of human breast and colon adenocarcinoma cell lines as models. The preference of ethaRAPTA base binding is in the order A > G > T > C. Once modified, the ethaRAPTA-induced BRCA1 structure has higher thermal stability than the modified equivalents of its related compound, RAPTA-C. EthaRAPTA exhibits a higher efficiency than RAPTA-C in inhibiting BRCA1 amplification. With respect to both compounds, the inhibition of BRCA1 amplification is more effective in an isolated system than in cell lines. These data provide evidence that will help to understand the process of elucidating the pathways involved in the response induced by ethaRAPTA. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

Binding of the Phage Display Derived Peptide CaIX-P1 on Human Colorectal Carcinoma Cells Correlates with the Expression of Carbonic Anhydrase IX

by Vasileios Askoxylakis, Volker Ehemann, Shoaib Rana, Susanne Krämer, Nuh N. Rahbari, Jürgen Debus and Uwe Haberkorn

Int. J. Mol. Sci. 2012, 13(10), 13030-13048; https://doi.org/10.3390/ijms131013030 - 11 Oct 2012

Cited by 9 | Viewed by 7493

Abstract

Phage display represents an attractive screening strategy for the identification of novel, specific binding ligands that could be used for tumor targeting. Recently, a new peptide (CaIX-P1) with affinity for human carbonic anhydrase IX (CAIX) was identified and evaluated. The aim of the [...] Read more.

Phage display represents an attractive screening strategy for the identification of novel, specific binding ligands that could be used for tumor targeting. Recently, a new peptide (CaIX-P1) with affinity for human carbonic anhydrase IX (CAIX) was identified and evaluated. The aim of the present study is to characterize the properties of CaIX-P1 for targeting human colorectal carcinoma and investigate the correlation of peptide binding with the expression of carbonic anhydrase IX. Human colorectal carcinoma HCT116 and HT29 cells were investigated for CAIX expression using Western Blot analysis. Binding and competition studies of ¹²⁵I-radiolabeled CaIX-P1 were performed on HCT116 cells in vitro. FACS analysis and fluorescence microscopy studies were carried out after cell incubation with fluorescein-labeled CaIX-P1 and rhodamine-labeled anti-human CAIX-mAb. Our studies revealed an enhanced in vitro expression of carbonic anhydrase IX in HCT116 and HT29 cells with increasing cell density. Binding of ¹²⁵I-labeled-CaIX-P1 on HCT116 cells increased with increasing cell density and correlated to the CAIX expression. FACS analysis demonstrated a correlation of cell labeling between FITC-CaIX-P1 and rhodamine-labeled anti-CAIX-mAb in both HCT116 and HT29 cells. The results of our study indicate that the phage display identified peptide CaIX-P1 might be an attractive candidate for the development of a ligand targeting CAIX in colorectal cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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966 KiB

Open AccessArticle

Effects of Genetically Engineered Stem Cells Expressing Cytosine Deaminase and Interferon-Beta or Carboxyl Esterase on the Growth of LNCaP Prostate Cancer Cells

by Bo-Rim Yi, Kyung-A. Hwang, Yun-Bae Kim, Seung U. Kim and Kyung-Chul Choi

Int. J. Mol. Sci. 2012, 13(10), 12519-12532; https://doi.org/10.3390/ijms131012519 - 28 Sep 2012

Cited by 15 | Viewed by 7433

Abstract

The risk of prostate cancer has been increasing in men by degrees. To develop a new prostate cancer therapy, we used a stem cell-derived gene directed prodrug enzyme system using human neural stem cells (hNSCs) that have a tumor-tropic effect. These hNSCs were [...] Read more.

The risk of prostate cancer has been increasing in men by degrees. To develop a new prostate cancer therapy, we used a stem cell-derived gene directed prodrug enzyme system using human neural stem cells (hNSCs) that have a tumor-tropic effect. These hNSCs were transduced with the therapeutic genes for bacterial cytosine deaminase (CD), alone or in combination with the one encoding human interferon-beta (IFN-β) or rabbit carboxyl esterase (CE) to generate HB1.F3.CD, HB1.F3.CD.IFN-β, and HB1.F3.CE cells, respectively. CD enzyme can convert the prodrug 5-fluorocytosine (5-FC) into the activated form 5-fluorouracil (5-FU). In addition, CE enzyme can convert the prodrug CPT-11 into a toxic agent, SN-38. In our study, the human stem cells were found to migrate toward LNCaP human prostate cancer cells rather than primary cells. This phenomenon may be due to interactions between chemoattractant ligands and receptors, such as VEGF/VEGFR2 and SCF/c-Kit, expressed as cancer and stem cells, respectively. The HB1.F3.CE, HB.F3.CD, or HB1.F3.CD.IFN-β cells significantly reduced the LNCaP cell viability in the presence of the prodrugs 5-FC or CPT-11. These results indicate that stem cells expressing therapeutic genes can be used to develop a new strategy for selectively treating human prostate cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

Anti-Epidermal Growth Factor Receptor (EGFR) Antibodies Overcome Resistance of Ovarian Cancer Cells to Targeted Therapy and Natural Cytotoxicity

by Nina Gottschalk, Rainer Kimmig, Stephan Lang, Mahavir Singh and Sven Brandau

Int. J. Mol. Sci. 2012, 13(9), 12000-12016; https://doi.org/10.3390/ijms130912000 - 20 Sep 2012

Cited by 25 | Viewed by 9801

Abstract

The poor outcome of advanced ovarian cancer under conventional therapy stimulated the exploration of new strategies to improve therapeutic efficacy. In our preclinical in vitro study we investigated a combination of targeted therapy and immunotherapy. Combination treatment with the anti-EGFR-antibody Cetuximab, related tyrosine [...] Read more.

The poor outcome of advanced ovarian cancer under conventional therapy stimulated the exploration of new strategies to improve therapeutic efficacy. In our preclinical in vitro study we investigated a combination of targeted therapy and immunotherapy. Combination treatment with the anti-EGFR-antibody Cetuximab, related tyrosine kinase inhibitors (TKI) and cytolytic NK cells was tested against different ovarian cancer cell lines and primary tumour cells cultured from patient ascites. We found that selected ovarian cancer cells were susceptible to cetuximab and anti-EGFR-TKI-treatment, while the majority of cell lines were resistant to single or combination treatment with both substances. In addition, most ovarian cancer cells displayed low susceptibility to natural cytotoxicity of unstimulated NK cells. Notably, NK cytotoxicity against resistant ovarian cancer cells could be effectively enhanced by addition of Cetuximab mediating antibody-dependent cellular cytotoxicity (ADCC). Neither natural cytotoxicity nor ADCC of NK cells were negatively affected by the presence of TKIs. ADCC could be further increased when NK cells were pre-stimulated with monocytes and the immunostimulatory mycobacterial protein PstS-1. Our data suggest that targeted antibody therapy could be beneficial even against resistant tumour cells by augmenting supplementary cytolytic NK functions. Future studies should evaluate the combination of targeted therapy and immunotherapeutic approaches in patients with advanced ovarian cancer being resistant to standard treatment. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells

by Friedemann Zengerling, Wolfgang Streicher, Andres J. Schrader, Mark Schrader, Bianca Nitzsche, Marcus V. Cronauer and Michael Höpfner

Int. J. Mol. Sci. 2012, 13(9), 11530-11542; https://doi.org/10.3390/ijms130911530 - 14 Sep 2012

Cited by 16 | Viewed by 7306

Abstract

Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa) is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR). A putative mechanism allowing prostate cancer (PCa) cells to grow under low levels of androgens, is the expression [...] Read more.

Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa) is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR). A putative mechanism allowing prostate cancer (PCa) cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD). Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

Tissue Microarray-Based Evaluation of Chromatin Assembly Factor-1 (CAF-1)/p60 as Tumour Prognostic Marker

by Massimo Mascolo, Gennaro Ilardi, Francesco Merolla, Daniela Russo, Maria Luisa Vecchione, Gaetano De Rosa and Stefania Staibano

Int. J. Mol. Sci. 2012, 13(9), 11044-11062; https://doi.org/10.3390/ijms130911044 - 5 Sep 2012

Cited by 23 | Viewed by 7380

Abstract

In this study we aimed to confirm the emerging role of Chromatin Assembly Factor 1 (CAF-1 p60) as a new proliferation and prognostic marker for cancer and to test the usefulness of the tissue microarray technique (TMA) for CAF-1 p60 rapid screening in [...] Read more.

In this study we aimed to confirm the emerging role of Chromatin Assembly Factor 1 (CAF-1 p60) as a new proliferation and prognostic marker for cancer and to test the usefulness of the tissue microarray technique (TMA) for CAF-1 p60 rapid screening in several human malignancies. CAF-1 is a histone chaperone, regulating chromatin dynamics during DNA replication and repair in eukaryotics. TMA is a powerful high-throughput methodology in the study of cancer, allowing simultaneous assessment of different biomarkers within large numbers of tissue specimens. We generated TMA taking 3 mm diameter-core biopsies from oral squamous cell carcinoma, prostate cancer, salivary gland tumours and skin melanoma specimens, which had been previously tested for CAF-1 p60 on routine tissue sections. We also analysed, for the first time, 30 larynx and 30 skin squamous cell carcinomas. CAF-1 p60 resulted over-expressed in both the tissue sections and the TMA specimens, with the highest levels of expression in tumours which were more aggressive and metastasizing. Notably, a high degree of agreement was found between the CAF-1 p60 assessment on TMAs and on routine tissue sections. Our findings confirm the prognostic role of CAF-1 p60 and indicate TMA as a really advantageous method for CAF-1 p60 immunohistochemical screening, allowing savings on both tissue quantity and operator-time. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

NAD(P)H:Quinone Oxidoreductase 1 (NQO1) P187S Polymorphism and Prostate Cancer Risk in Caucasians

by Christine G. Stoehr, Elke Nolte, Sven Wach, Wolf F. Wieland, Ferdinand Hofstaedter, Arndt Hartmann and Robert Stoehr

Int. J. Mol. Sci. 2012, 13(9), 10959-10969; https://doi.org/10.3390/ijms130910959 - 31 Aug 2012

Cited by 14 | Viewed by 7241

Abstract

NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyses the reduction of quinoid compounds to hydroquinones, preventing the generation of free radicals and reactive oxygen. A “C” to “T” transversion at position 609 of NQO1, leading to a nonsynonymous amino acid change (Pro187Ser, P187S), results in [...] Read more.

NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyses the reduction of quinoid compounds to hydroquinones, preventing the generation of free radicals and reactive oxygen. A “C” to “T” transversion at position 609 of NQO1, leading to a nonsynonymous amino acid change (Pro187Ser, P187S), results in an altered enzyme activity. No NQO1 protein activity was detected in NQO1 ⁶⁰⁹TT genotype, and low to intermediate activity was detected in NQO1 ⁶⁰⁹CT genotype compared with ⁶⁰⁹CC genotype. Thus, this polymorphism may result in altered cancer predisposition. For prostate cancer, only sparse data are available. We therefore analyzed the distribution of the NQO1 P187S SNP (single nucleotide polymorphism) in prostate cancer patients and a healthy control group. Allelic variants were determined using RFLP analysis. Overall, 232 patients without any malignancy and 119 consecutive prostate cancer patients were investigated. The genotype distribution in our cohorts followed the Hardy–Weinberg equilibrium in cases and controls. The distribution of the NQO1 codon 187 SNP did not differ significantly between prostate cancer patients and the control group (p = 0.242). There was also no association between the allelic variants and stage or Gleason score of the tumors. The NQO1 P187S SNP was not significantly associated with an increased prostate cancer risk in our cohorts. The SNP has also no influence on histopathological characteristics of the tumors. A combined analysis of all available data from published European studies also showed no significant differences in the genotype distribution between controls and prostate cancer patients. Our data suggest a minor role of the NQO1 nucleotide 609 polymorphism in prostate carcinogenesis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessArticle

Combined Treatment with an Oncolytic Adenovirus and Antitumor Activity of Vincristine against Retinoblastoma Cells

by Xin Song, Haibo Wang, Renbing Jia, Biyun Cun, Xiaoping Zhao, Yixiong Zhou, Xiaofang Xu, Guanxiang Qian, Shengfang Ge and Xianqun Fan

Int. J. Mol. Sci. 2012, 13(9), 10736-10749; https://doi.org/10.3390/ijms130910736 - 27 Aug 2012

Cited by 11 | Viewed by 6908

Abstract

Treatment trends of retinoblastoma (RB) have gradually evolved from eye enucleation and external radiation to local treatment. Combined treatment with an oncolytic virus and chemotherapy is currently a new method in RB treatment. To investigate the therapeutic effect of oncolytic adenovirus SG600 in [...] Read more.

Treatment trends of retinoblastoma (RB) have gradually evolved from eye enucleation and external radiation to local treatment. Combined treatment with an oncolytic virus and chemotherapy is currently a new method in RB treatment. To investigate the therapeutic effect of oncolytic adenovirus SG600 in combination with vincristine (VCR) on retinoblastoma in vitro, the cell viability, cell cycle effects and apoptotic activity of HXO-RB₄₄ cells treated with SG600, VCR or SG600 plus VCR were measured using a cell counting kit-8-based procedure and flow cytometry. Western blot analysis for Akt, p-Akt, p-p53 and p-Rb protein was performed to investigate the underlying mechanisms of combined therapy. The combination therapy exerted a synergistic antitumor effect via a type of G₂/M and S phase arrest rather than the induction of apoptosis. The combination of VCR and SG600 further reduced Akt phosphorylation compared with cells treated with VCR alone, suggesting that SG600 could overcome chemoresistance, perhaps by down-regulating Akt in RB cells. An increase in the expression of p-p53 and decrease in p-Rb expression in HXO-RB₄₄ after co-treatment might be associated with cell cycle block. Western blot examination revealed that VCR might enhance SG600 replication. These results suggest that viro-chemo combination therapy is a feasible and potentially promising approach for the treatment of retinoblastoma. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Helicobacter pylori Disrupts Host Cell Membranes, Initiating a Repair Response and Cell Proliferation

by Li-Ling Lin, Hsuan-Cheng Huang, Satoshi Ogihara, Jin-Town Wang, Meng-Chuan Wu, Paul L. McNeil, Chiung-Nien Chen and Hsueh-Fen Juan

Int. J. Mol. Sci. 2012, 13(8), 10176-10192; https://doi.org/10.3390/ijms130810176 - 15 Aug 2012

Cited by 17 | Viewed by 8425

Abstract

Helicobacter pylori (H. pylori), the human stomach pathogen, lives on the inner surface of the stomach and causes chronic gastritis, peptic ulcer, and gastric cancer. Plasma membrane repair response is a matter of life and death for human cells against physical [...] Read more.

Helicobacter pylori (H. pylori), the human stomach pathogen, lives on the inner surface of the stomach and causes chronic gastritis, peptic ulcer, and gastric cancer. Plasma membrane repair response is a matter of life and death for human cells against physical and biological damage. We here test the hypothesis that H. pylori also causes plasma membrane disruption injury, and that not only a membrane repair response but also a cell proliferation response are thereby activated. Vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A (CagA) have been considered to be major H. pylori virulence factors. Gastric cancer cells were infected with H. pylori wild type (vacA+/cagA+), single mutant (ΔvacA or ΔcagA) or double mutant (ΔvacA/ΔcagA) strains and plasma membrane disruption events and consequent activation of membrane repair components monitored. H. pylori disrupts the host cell plasma membrane, allowing localized dye and extracellular Ca²⁺ influx. Ca²⁺-triggered members of the annexin family, A1 and A4, translocate, in response to injury, to the plasma membrane, and cell surface expression of an exocytotic maker of repair, LAMP-2, increases. Additional forms of plasma membrane disruption, unrelated to H. pylori exposure, also promote host cell proliferation. We propose that H. pylori activation of a plasma membrane repair is pro-proliferative. This study might therefore provide new insight into potential mechanisms of H. pylori-induced gastric carcinogenesis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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MicroRNA-125b Functions as a Tumor Suppressor in Hepatocellular Carcinoma Cells

by Hong-Yan Jia, Yu-Xuan Wang, Wen-Ting Yan, Hui-Yu Li, Yan-Zhang Tian, Shi-Ming Wang and Hao-Liang Zhao

Int. J. Mol. Sci. 2012, 13(7), 8762-8774; https://doi.org/10.3390/ijms13078762 - 16 Jul 2012

Cited by 75 | Viewed by 8433

Abstract

MicroRNAs (miRNAs) are important regulators of multiple cellular processes, and the deregulation of miRNA is a common event in diverse human diseases, particularly cancer. However, the mechanisms underlying the relationship between disordered miRNA expression and tumorigenesis have remained largely unknown. In this study, [...] Read more.

MicroRNAs (miRNAs) are important regulators of multiple cellular processes, and the deregulation of miRNA is a common event in diverse human diseases, particularly cancer. However, the mechanisms underlying the relationship between disordered miRNA expression and tumorigenesis have remained largely unknown. In this study, we demonstrated the down-regulation of miR-125b in hepatocellular carcinoma (HCC) tissues and HCC cell lines by Northern blot and quantitative RT-PCR analyses. The ectopic expression of miR-125b reduced the cellular proliferation and cell cycle progression of HCC cells by targeting Mcl-1 and IL6R. Furthermore, the miR-125b-induced inhibition of cell proliferation was rescued by the expression of Mcl-1 or IL6R variants that lacked 3' UTRs. Thus, this study revealed the differential expression of miR-125b in HCC cells and elucidated its potential as a tumor suppressor in HCC development. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Chemopreventive Efficacy of Atorvastatin against Nitrosamine-Induced Rat Bladder Cancer: Antioxidant, Anti-Proliferative and Anti-Inflammatory Properties

by Belmiro Parada, Flávio Reis, Ângela Pinto, José Sereno, Maria Xavier-Cunha, Paula Neto, Petronila Rocha-Pereira, Alfredo Mota, Arnaldo Figueiredo and Frederico Teixeira

Int. J. Mol. Sci. 2012, 13(7), 8482-8499; https://doi.org/10.3390/ijms13078482 - 9 Jul 2012

Cited by 28 | Viewed by 8667

Abstract

To investigate the anti-carcinogenic effects of Atorvastatin (Atorva) on a rat bladder carcinogenesis model with N-butyl-N-(4-hydroxibutil)nitrosamine (BBN), four male Wistar rat groups were studied: (1) Control: vehicle; (2) Atorva: 3 mg/kg bw/day; (3) Carcinogen: BBN (0.05%); (4) Preventive Atorva: [...] Read more.

To investigate the anti-carcinogenic effects of Atorvastatin (Atorva) on a rat bladder carcinogenesis model with N-butyl-N-(4-hydroxibutil)nitrosamine (BBN), four male Wistar rat groups were studied: (1) Control: vehicle; (2) Atorva: 3 mg/kg bw/day; (3) Carcinogen: BBN (0.05%); (4) Preventive Atorva: 3 mg/kg bw/day Atorva + BBN. A two phase protocol was used, in which the drug and the carcinogen were given between week 1 and 8 and tumor development or chemoprevention were expressed between week 9 and 20, when the bladders were collected for macroscopic, histological and immunohistochemical (p53, ki67, CD31) evaluation. Serum was assessed for markers of inflammation, proliferation and redox status. The incidence of bladder carcinoma was: control 0/8 (0%); Atorva 0/8 (0%); BBN 13/20 (65%) and Atorva + BBN 1/8 (12.5%). The number and volume of tumors were significantly lower in the Atorva + BBN group, with a marked reduction in hyperplasia, dysplasia and carcinoma in situ lesions. An anti-proliferative, anti-inflammatory and antioxidant profile was also observed in the preventive Atorva group. p53 and ki67 immunostaining were significantly increased in the BBN-treated rats, which was prevented in the Atorva + BBN group. No differences were found for CD31 expression. In conclusion, Atorvastatin had a clear inhibitory effect on bladder cancer development, probably due to its antioxidant, anti-proliferative and anti-inflammatory properties. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Clinical Relevance of CDH1 and CDH13 DNA-Methylation in Serum of Cervical Cancer Patients

by Abida Abudukadeer, Rania Bakry, Georg Goebel, Irene Mutz-Dehbalaie, Andreas Widschwendter, Günther K. Bonn and Heidi Fiegl

Int. J. Mol. Sci. 2012, 13(7), 8353-8363; https://doi.org/10.3390/ijms13078353 - 5 Jul 2012

Cited by 31 | Viewed by 8359

Abstract

This study was designed to investigate the DNA-methylation status of E-cadherin (CDH1) and H-cadherin (CDH13) in serum samples of cervical cancer patients and control patients with no malignant diseases and to evaluate the clinical utility of these [...] Read more.

This study was designed to investigate the DNA-methylation status of E-cadherin (CDH1) and H-cadherin (CDH13) in serum samples of cervical cancer patients and control patients with no malignant diseases and to evaluate the clinical utility of these markers. DNA-methylation status of CDH1 and CDH13 was analyzed by means of MethyLight-technology in serum samples from 49 cervical cancer patients and 40 patients with diseases other than cancer. To compare this methylation analysis with another technique, we analyzed the samples with a denaturing high performance liquid chromatography (DHPLC) PCR-method. The specificity and sensitivity of CDH1 DNA-methylation measured by MethyLight was 75% and 55%, and for CDH13 DNA-methylation 95% and 10%. We identified a specificity of 92.5% and a sensitivity of only 27% for the CDH1 DHPLC-PCR analysis. Multivariate analysis showed that serum CDH1 methylation-positive patients had a 7.8-fold risk for death (95% CI: 2.2–27.7; p = 0.001) and a 92.8-fold risk for relapse (95% CI: 3.9–2207.1; p = 0.005). We concluded that the serological detection of CDH1 and CDH13 DNA-hypermethylation is not an ideal diagnostic tool due to low diagnostic specificity and sensitivity. However, it was validated that CDH1 methylation analysis in serum samples may be of potential use as a prognostic marker for cervical cancer patients. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Genome-Wide Analysis of DNA Methylation and Expression of MicroRNAs in Breast Cancer Cells

by Sumiyo Morita, Ryou-u Takahashi, Riu Yamashita, Atsushi Toyoda, Takuro Horii, Mika Kimura, Asao Fujiyama, Kenta Nakai, Shoji Tajima, Ryo Matoba, Takahiro Ochiya and Izuho Hatada

Int. J. Mol. Sci. 2012, 13(7), 8259-8272; https://doi.org/10.3390/ijms13078259 - 3 Jul 2012

Cited by 37 | Viewed by 10813

Abstract

DNA methylation of promoters is linked to transcriptional silencing of protein-coding genes, and its alteration plays important roles in cancer formation. For example, hypermethylation of tumor suppressor genes has been seen in some cancers. Alteration of methylation in the promoters of microRNAs (miRNAs) [...] Read more.

DNA methylation of promoters is linked to transcriptional silencing of protein-coding genes, and its alteration plays important roles in cancer formation. For example, hypermethylation of tumor suppressor genes has been seen in some cancers. Alteration of methylation in the promoters of microRNAs (miRNAs) has also been linked to transcriptional changes in cancers; however, no systematic studies of methylation and transcription of miRNAs have been reported. In the present study, to clarify the relation between DNA methylation and transcription of miRNAs, next-generation sequencing and microarrays were used to analyze the methylation and expression of miRNAs, protein-coding genes, other non-coding RNAs (ncRNAs), and pseudogenes in the human breast cancer cell lines MCF7 and the adriamycin (ADR) resistant cell line MCF7/ADR. DNA methylation in the proximal promoter of miRNAs is tightly linked to transcriptional silencing, as it is with protein-coding genes. In protein-coding genes, highly expressed genes have CpG-rich proximal promoters whereas weakly expressed genes do not. This is only rarely observed in other gene categories, including miRNAs. The present study highlights the epigenetic similarities and differences between miRNA and protein-coding genes. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Expression of Sox2 and Oct4 and Their Clinical Significance in Human Non-Small-Cell Lung Cancer

by Xinxin Li, Jinguang Wang, Zhiyun Xu, Aftab Ahmad, Encheng Li, Yuan Wang, Suli Qin and Qi Wang

Int. J. Mol. Sci. 2012, 13(6), 7663-7675; https://doi.org/10.3390/ijms13067663 - 21 Jun 2012

Cited by 91 | Viewed by 9586

Abstract

Sox2 and Oct4 are transcription factors with the characteristics of regulating self-renewal and differentiation of embryonic stem cell. The aim of this study was to detect the expression of Sox2 and Oct4 and analyze their clinical significance in human non-small-cell lung cancer (NSCLC). [...] Read more.

Sox2 and Oct4 are transcription factors with the characteristics of regulating self-renewal and differentiation of embryonic stem cell. The aim of this study was to detect the expression of Sox2 and Oct4 and analyze their clinical significance in human non-small-cell lung cancer (NSCLC). Expression of Sox2 and Oct4 were assayed in cancer tissues and their corresponding paracancerous tissues from 44 patients with NSCLC and 21 patients with benign tumors using immunohistochemistry, Western blot, reverse transcription polymerase chain reaction (RT-PCR). The correlation between the expression of Sox2 and Oct4 and tumor type, grade and prognosis and the utility of the two genes in discriminating between benign and malignant tumors were analyzed as well. The results showed that Sox2 and Oct4 positive staining was only seen in the nuclei of cancer cells but not in either the precancerous tissues or benign tumor tissues by immunohistochemistry (p < 0.01). Furthermore, in the lung cancer tissue, the positive rate for Sox2 and Oct4 was 70.5% and 54.5%, respectively. Meanwhile, clinicopathological correlations showed that the Oct4 expression level was significantly associated with poorer differentiation and higher TNM stage of the cancer (p < 0.05). Western blot and RT-PCR analysis showed similar results to immunohistochemistry. Follow-up analysis revealed that expression of Oct4 was significantly associated with poor prognosis of lung cancer. The conclusion is that Sox2 and Oct4 may act as the promising unit markers in directing NSCLC diagnosis and therapy. Also, Oct4 can be regarded as a novel predictor of poor prognosis for NSCLC patients undergoing resection. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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O6-Methylguanine-Methyltransferase (MGMT) Promoter Methylation Status in Glioma Stem-Like Cells is Correlated to Temozolomide Sensitivity Under Differentiation-Promoting Conditions

by Claire Villalva, Ulrich Cortes, Michel Wager, Jean-Marc Tourani, Pierre Rivet, Celine Marquant, Sebastien Martin, Ali G. Turhan and Lucie Karayan-Tapon

Int. J. Mol. Sci. 2012, 13(6), 6983-6994; https://doi.org/10.3390/ijms13066983 - 7 Jun 2012

Cited by 44 | Viewed by 8386

Abstract

Glioblastoma (GBM) is the most malignant type of primary brain tumor with a very poor prognosis. The actual standard protocol of treatment for GBM patients consists of radiotherapy and concomitant temozolomide (TMZ). However, the therapeutic efficacy of this treatment is limited due to [...] Read more.

Glioblastoma (GBM) is the most malignant type of primary brain tumor with a very poor prognosis. The actual standard protocol of treatment for GBM patients consists of radiotherapy and concomitant temozolomide (TMZ). However, the therapeutic efficacy of this treatment is limited due to tumor recurrence and TMZ resistance. Recently isolated, glioma stem-like cells (GSCs) are thought to represent the population of tumorigenic cells responsible for GBM resistance and recurrence following surgery and chemotherapy. In addition, MGMT (O6-methylguanine-methyltransferase) methylation is considered as one of the principal mechanisms contributing to TMZ sensitivity of GBM. In this study we have isolated GSCs from 10 adult GBM patients and investigated the relationship between MGMT methylation status and Temozolomide (TMZ) sensitivity of these lines grown either in stem-like or differentiation promoting conditions. Sensitivity to TMZ was significantly associated with MGMT methylation status in cells committed to differentiation but not in stem-like cells. In addition, patients harboring highly methylated MGMT promoters had a longer overall survival. These results reveal the importance of the differentiation process when considering the predictive value of MGMT status in GSCs for clinical response to TMZ. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Role of Helicity on the Anticancer Mechanism of Action of Cationic-Helical Peptides

by Yi-Bing Huang, Li-Yan He, Hong-Yu Jiang and Yu-Xin Chen

Int. J. Mol. Sci. 2012, 13(6), 6849-6862; https://doi.org/10.3390/ijms13066849 - 5 Jun 2012

Cited by 48 | Viewed by 7945

Abstract

In the present study, the 26-residue amphipathic α-helical peptide A12L/A20L (Ac-KWKSFLKTFKSLKKTVLHTLLKAISS-amide) with strong anticancer activity and specificity was used as the framework to study the effects of helicity of α-helical anticancer peptides on biological activities. Helicity was systematically modulated by introducing D-amino acids [...] Read more.

In the present study, the 26-residue amphipathic α-helical peptide A12L/A20L (Ac-KWKSFLKTFKSLKKTVLHTLLKAISS-amide) with strong anticancer activity and specificity was used as the framework to study the effects of helicity of α-helical anticancer peptides on biological activities. Helicity was systematically modulated by introducing D-amino acids to replace the original L-amino acids on the non-polar face or the polar face of the helix. Peptide helicity was measured by circular dichroism spectroscopy and was demonstrated to correlate with peptide hydrophobicity and the number of D-amino acid substitutions. Biological studies showed that strong hemolytic activity of peptides generally correlated with high hydrophobicity and helicity. Lower helicity caused the decrease of anti-HeLa activity of peptides. By introducing D-amino acids to replace the original L-amino acids on the non-polar face or the polar face of the helix, we improved the therapeutic index of A12L/A20L against HeLa cells by 9-fold and 22-fold, respectively. These results show that the helicity of anticancer peptides plays a crucial role for biological activities. This specific rational approach of peptide design could be a powerful method to improve the specificity of anticancer peptides as promising therapeutics in clinical practices. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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CD146 Expression Correlates with Epithelial-Mesenchymal Transition Markers and a Poor Prognosis in Gastric Cancer

by Wen-Fang Liu, Shu-Rong Ji, Jian-Jun Sun, Yi Zhang, Zhong-Yan Liu, Ai-Bin Liang and Hua-Zong Zeng

Int. J. Mol. Sci. 2012, 13(5), 6399-6406; https://doi.org/10.3390/ijms13056399 - 23 May 2012

Cited by 70 | Viewed by 8468

Abstract

CD146 has been regarded as a novel potential therapeutic target for multiple cancers. The aim of the study was to investigate the expression of CD146 in gastric cancer and evaluate its clinical-pathological and prognostic significance. The expression of CD146 and three epithelial-mesenchymal transition [...] Read more.

CD146 has been regarded as a novel potential therapeutic target for multiple cancers. The aim of the study was to investigate the expression of CD146 in gastric cancer and evaluate its clinical-pathological and prognostic significance. The expression of CD146 and three epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, β-catenin and vimentin) was examined in 144 gastric cancers by immunohistochemistry. Fifty-nine cases (41.0%) were defined as positive for CD146 expression. We found that CD146 expression correlated positively with lymph node involvement and a poor prognosis, and retained an independent prognostic factor for gastric cancer patients. Furthermore, positive expression of CD146 was strongly associated with loss of the epithelial marker E-cadherin and acquisition of the expression of the mesenchymal markers nuclear β-catenin and vimentin. These findings suggest that CD146 might promote EMT and progression in gastric cancer, and thus may be a potential therapeutic target for patients with gastric cancers. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Revealing the Anti-Tumor Effect of Artificial miRNA p-27-5p on Human Breast Carcinoma Cell Line T-47D

by Chien-Wei Tseng, Hsuan-Cheng Huang, Arthur Chun-Chieh Shih, Ya-Ya Chang, Chung-Cheng Hsu, Jen-Yun Chang, Wen-Hsiung Li and Hsueh-Fen Juan

Int. J. Mol. Sci. 2012, 13(5), 6352-6369; https://doi.org/10.3390/ijms13056352 - 23 May 2012

Cited by 5 | Viewed by 9536

Abstract

microRNAs (miRNAs) cause mRNA degradation or translation suppression of their target genes. Previous studies have found direct involvement of miRNAs in cancer initiation and progression. Artificial miRNAs, designed to target single or multiple genes of interest, provide a new therapeutic strategy for cancer. [...] Read more.

microRNAs (miRNAs) cause mRNA degradation or translation suppression of their target genes. Previous studies have found direct involvement of miRNAs in cancer initiation and progression. Artificial miRNAs, designed to target single or multiple genes of interest, provide a new therapeutic strategy for cancer. This study investigates the anti-tumor effect of a novel artificial miRNA, miR P-27-5p, on breast cancer. In this study, we reveal that miR P-27-5p downregulates the differential gene expressions associated with the protein modification process and regulation of cell cycle in T-47D cells. Introduction of this novel artificial miRNA, miR P-27-5p, into breast cell lines inhibits cell proliferation and induces the first “gap” phase (G1) cell cycle arrest in cancer cell lines but does not affect normal breast cells. We further show that miR P-27-5p targets the 3′-untranslated mRNA region (3′-UTR) of cyclin-dependent kinase 4 (CDK4) and reduces both the mRNA and protein level of CDK4, which in turn, interferes with phosphorylation of the retinoblastoma protein (RB1). Overall, our data suggest that the effects of miR p-27-5p on cell proliferation and G1 cell cycle arrest are through the downregulation of CDK4 and the suppression of RB1 phosphorylation. This study opens avenues for future therapies targeting breast cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Characterization of ARF-BP1/HUWE1 Interactions with CTCF, MYC, ARF and p53 in MYC-Driven B Cell Neoplasms

by Chen-Feng Qi, Yong-Soo Kim, Shao Xiang, Ziedulla Abdullaev, Ted A. Torrey, Siegfried Janz, Alexander L. Kovalchuk, Jiafang Sun, Delin Chen, William C. Cho, Wei Gu and Herbert C. Morse III

Int. J. Mol. Sci. 2012, 13(5), 6204-6219; https://doi.org/10.3390/ijms13056204 - 21 May 2012

Cited by 27 | Viewed by 9674

Abstract

Transcriptional activation of MYC is a hallmark of many B cell lineage neoplasms. MYC provides a constitutive proliferative signal but can also initiate ARF-dependent activation of p53 and apoptosis. The E3 ubiquitin ligase, ARF-BP1, encoded by HUWE1, modulates the activity of both [...] Read more.

Transcriptional activation of MYC is a hallmark of many B cell lineage neoplasms. MYC provides a constitutive proliferative signal but can also initiate ARF-dependent activation of p53 and apoptosis. The E3 ubiquitin ligase, ARF-BP1, encoded by HUWE1, modulates the activity of both the MYC and the ARF-p53 signaling pathways, prompting us to determine if it is involved in the pathogenesis of MYC-driven B cell lymphomas. ARF-BP1 was expressed at high levels in cell lines from lymphomas with either wild type or mutated p53 but not in ARF-deficient cells. Downregulation of ARF-BP1 resulted in elevated steady state levels of p53, growth arrest and apoptosis. Co-immunoprecipitation studies identified a multiprotein complex comprised of ARF-BP1, ARF, p53, MYC and the multifunctional DNA-binding factor, CTCF, which is involved in the transcriptional regulation of MYC, p53 and ARF. ARF-BP1 bound and ubiquitylated CTCF leading to its proteasomal degradation. ARF-BP1 and CTCF thus appear to be key cofactors linking the MYC proliferative and p53-ARF apoptotic pathways. In addition, ARF-BP1 could be a therapeutic target for MYC-driven B lineage neoplasms, even if p53 is inactive, with inhibition reducing the transcriptional activity of MYC for its target genes and stabilizing the apoptosis-promoting activities of p53. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Evaluation of HER2 Gene Amplification in Breast Cancer Using Nuclei Microarray in Situ Hybridization

by Huiyong Jiang, Xiaoyan Bai, Cheng Zhang and Xuefeng Zhang

Int. J. Mol. Sci. 2012, 13(5), 5519-5527; https://doi.org/10.3390/ijms13055519 - 8 May 2012

Cited by 6 | Viewed by 10821

Abstract

Fluorescence in situ hybridization (FISH) assay is considered the “gold standard” in evaluating HER2/neu (HER2) gene status. However, FISH detection is costly and time consuming. Thus, we established nuclei microarray with extracted intact nuclei from paraffin embedded breast cancer tissues for FISH detection. [...] Read more.

Fluorescence in situ hybridization (FISH) assay is considered the “gold standard” in evaluating HER2/neu (HER2) gene status. However, FISH detection is costly and time consuming. Thus, we established nuclei microarray with extracted intact nuclei from paraffin embedded breast cancer tissues for FISH detection. The nuclei microarray FISH (NMFISH) technology serves as a useful platform for analyzing HER2 gene/chromosome 17 centromere ratio. We examined HER2 gene status in 152 cases of invasive ductal carcinomas of the breast that were resected surgically with FISH and NMFISH. HER2 gene amplification status was classified according to the guidelines of the American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP). Comparison of the cut-off values for HER2/chromosome 17 centromere copy number ratio obtained by NMFISH and FISH showed that there was almost perfect agreement between the two methods (κ coefficient 0.920). The results of the two methods were almost consistent for the evaluation of HER2 gene counts. The present study proved that NMFISH is comparable with FISH for evaluating HER2 gene status. The use of nuclei microarray technology is highly efficient, time and reagent conserving and inexpensive. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Evaluation of the Adenocarcinoma-Associated Gene AGR2 and the Intestinal Stem Cell Marker LGR5 as Biomarkers in Colorectal Cancer

by Manuel Valladares-Ayerbes, Moisés Blanco-Calvo, Margarita Reboredo, María J. Lorenzo-Patiño, Pilar Iglesias-Díaz, Mar Haz, Silvia Díaz-Prado, Vanessa Medina, Isabel Santamarina, Sonia Pértega, Angélica Figueroa and Luis M. Antón-Aparicio

Int. J. Mol. Sci. 2012, 13(4), 4367-4387; https://doi.org/10.3390/ijms13044367 - 5 Apr 2012

Cited by 41 | Viewed by 10107

Abstract

We aim to estimate the diagnostic performances of anterior gradient homolog-2 (AGR2) and Leucine-rich repeat-containing-G-protein-coupled receptor 5 (LGR5) in peripheral blood (PB) as mRNA biomarkers in colorectal cancer (CRC) and to explore their prognostic significance. Real-time PCR was used [...] Read more.

We aim to estimate the diagnostic performances of anterior gradient homolog-2 (AGR2) and Leucine-rich repeat-containing-G-protein-coupled receptor 5 (LGR5) in peripheral blood (PB) as mRNA biomarkers in colorectal cancer (CRC) and to explore their prognostic significance. Real-time PCR was used to analyze AGR2 and LGR5 in 54 stages I-IV CRC patients and 19 controls. Both mRNAs were significantly increased in PB from CRC patients compared to controls. The area under the receiver-operating characteristic curves were 0.722 (p = 0.006), 0.376 (p = 0.123) and 0.767 (p = 0.001) for AGR2, LGR5 and combined AGR2/LGR5, respectively. The AGR2/LGR5 assay resulted in 67.4% sensitivity and 94.7% specificity. AGR2 correlated with pT3–pT4 and high-grade tumors. LGR5 correlated with metastasis, R2 resections and high-grade. The progression-free survival (PFS) of patients with high AGR2 was reduced (p = 0.037; HR, 2.32), also in the stage I-III subgroup (p = 0.046). LGR5 indicated a poor prognosis regarding both PFS (p = 0.007; HR, 1.013) and overall survival (p = 0.045; HR, 1.01). High AGR2/LGR5 was associated with poor PFS (p = 0.014; HR, 2.8) by multivariate analysis. Our findings indicate that the assessment of AGR2 and LGR5 in PB might reflect the presence of circulating tumor cells (CTC) and stem cell like CTC in CRC. Increased AGR2 and LGR5 are associated with poor outcomes. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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MicroRNAs Involved in Anti-Tumour Immunity

by Hong W. H. Yu, Daniel M. Y. Sze and William C. S. Cho

Int. J. Mol. Sci. 2013, 14(3), 5587-5607; https://doi.org/10.3390/ijms14035587 - 11 Mar 2013

Cited by 14 | Viewed by 7549

Abstract

MicroRNAs (miRNAs) are a category of small RNAs that constitute a new layer of complexity to gene regulation within the cell, which has provided new perspectives in understanding cancer biology. The deregulation of miRNAs contributes critically to the development and pathophysiology of a [...] Read more.

MicroRNAs (miRNAs) are a category of small RNAs that constitute a new layer of complexity to gene regulation within the cell, which has provided new perspectives in understanding cancer biology. The deregulation of miRNAs contributes critically to the development and pathophysiology of a number of cancers. miRNAs have been found to participate in cell transformation and multiplication by acting as tumour oncogenes or suppressors; therefore, harnessing miRNAs may provide promising cancer therapeutics. Another major function of miRNAs is their activity as critical regulatory vehicles eliciting important regulatory processes in anti-tumour immunity through their influence on the development, differentiation and activation of various immune cells of both innate and adaptive immunity. This review aims to summarise recent findings focusing on the regulatory mechanisms of the development, differentiation, and proliferative aspects of the major immune populations by a diverse profile of miRNAs and may enrich our current understanding of the involvement of miRNAs in anti-tumour immunity. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Chemical Inhibitors and microRNAs (miRNA) Targeting the Mammalian Target of Rapamycin (mTOR) Pathway: Potential for Novel Anticancer Therapeutics

by Naif AlQurashi, Saeed M. Hashimi and Ming Q. Wei

Int. J. Mol. Sci. 2013, 14(2), 3874-3900; https://doi.org/10.3390/ijms14023874 - 13 Feb 2013

Cited by 37 | Viewed by 11601

Abstract

The mammalian target of rapamycin (mTOR) is a critical regulator of many fundamental features in response to upstream cellular signals, such as growth factors, energy, stress and nutrients, controlling cell growth, proliferation and metabolism through two complexes, mTORC1 and mTORC2. Dysregulation of mTOR [...] Read more.

The mammalian target of rapamycin (mTOR) is a critical regulator of many fundamental features in response to upstream cellular signals, such as growth factors, energy, stress and nutrients, controlling cell growth, proliferation and metabolism through two complexes, mTORC1 and mTORC2. Dysregulation of mTOR signalling often occurs in a variety of human malignant diseases making it a crucial and validated target in the treatment of cancer. Tumour cells have shown high susceptibility to mTOR inhibitors. Rapamycin and its derivatives (rapalogs) have been tested in clinical trials in several tumour types and found to be effective as anticancer agents in patients with advanced cancers. To block mTOR function, they form a complex with FKBP12 and then bind the FRB domain of mTOR. Furthermore, a new generation of mTOR inhibitors targeting ATP-binding in the catalytic site of mTOR showed potent and more selective inhibition. More recently, microRNAs (miRNA) have emerged as modulators of biological pathways that are essential in cancer initiation, development and progression. Evidence collected to date shows that miRNAs may function as tumour suppressors or oncogenes in several human neoplasms. The mTOR pathway is a promising target by miRNAs for anticancer therapy. Extensive studies have indicated that regulation of the mTOR pathway by miRNAs plays a major role in cancer progression, indicating a novel way to investigate the tumorigenesis and therapy of cancer. Here, we summarize current findings of the role of mTOR inhibitors and miRNAs in carcinogenesis through targeting mTOR signalling pathways and determine their potential as novel anti-cancer therapeutics. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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HGF–MET Cascade, a Key Target for Inhibiting Cancer Metastasis: The Impact of NK4 Discovery on Cancer Biology and Therapeutics

by Shinya Mizuno and Toshikazu Nakamura

Int. J. Mol. Sci. 2013, 14(1), 888-919; https://doi.org/10.3390/ijms14010888 - 7 Jan 2013

Cited by 44 | Viewed by 11041

Abstract

Hepatocyte growth factor (HGF) was discovered in 1984 as a mitogen of rat hepatocytes in a primary culture system. In the mid-1980s, MET was identified as an oncogenic mutant protein that induces malignant phenotypes in a human cell line. In the early 1990s, [...] Read more.

Hepatocyte growth factor (HGF) was discovered in 1984 as a mitogen of rat hepatocytes in a primary culture system. In the mid-1980s, MET was identified as an oncogenic mutant protein that induces malignant phenotypes in a human cell line. In the early 1990s, wild-type MET was shown to be a functional receptor of HGF. Indeed, HGF exerts multiple functions, such as proliferation, morphogenesis and anti-apoptosis, in various cells via MET tyrosine kinase phosphorylation. During the past 20 years, we have accumulated evidence that HGF is an essential conductor for embryogenesis and tissue regeneration in various types of organs. Furthermore, we found in the mid-1990s that stroma-derived HGF is a major contributor to cancer invasion at least in vitro. Based on this background, we prepared NK4 as an antagonist of HGF: NK4 inhibits HGF-mediated MET tyrosine phosphorylation by competing with HGF for binding to MET. In vivo, NK4 treatments produced the anti-tumor outcomes in mice bearing distinct types of malignant cancers, associated with the loss in MET activation. There are now numerous reports showing that HGF-antagonists and MET-inhibitors are logical for inhibiting tumor growth and metastasis. Additionally, NK4 exerts anti-angiogenic effects, partly through perlecan-dependent cascades. This paper focuses on the chronology and significance of HGF-antagonisms in anti-tumor researches, with an interest in NK4 discovery. Tumor HGF–MET axis is now critical for drug resistance and cancer stem cell maintenance. Thus, oncologists cannot ignore this cascade for the future success of anti-metastatic therapy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance

by Rocío García-Becerra, Nancy Santos, Lorenza Díaz and Javier Camacho

Int. J. Mol. Sci. 2013, 14(1), 108-145; https://doi.org/10.3390/ijms14010108 - 20 Dec 2012

Cited by 214 | Viewed by 17817

Abstract

Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERα-positive breast cancer. Alone or combined with chemotherapy, [...] Read more.

Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERα-positive breast cancer. Alone or combined with chemotherapy, tamoxifen significantly reduces disease progression and is associated with more favorable impact on survival in patients. Unfortunately, endocrine resistance occurs, either de novo or acquired during the course of the treatment. The mechanisms that contribute to hormonal resistance include loss or modification in the ERα expression, regulation of signal transduction pathways, altered expression of specific microRNAs, balance of co-regulatory proteins, and genetic polymorphisms involved in tamoxifen metabolic activity. Because of the clinical consequences of endocrine resistance, new treatment strategies are arising to make the cells sensitive to tamoxifen. Here, we will review the current knowledge on mechanisms of endocrine resistance in breast cancer cells. In addition, we will discuss novel therapeutic strategies to overcome such resistance. Undoubtedly, circumventing endocrine resistance should help to improve therapy for the benefit of breast cancer patients. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Novel Molecular Targets for the Treatment of Gastroenteropancreatic Endocrine Tumors: Answers and Unsolved Problems

by Gabriele Capurso, Volker Fendrich, Maria Rinzivillo, Francesco Panzuto, Detlef K. Bartsch and Gianfranco Delle Fave

Int. J. Mol. Sci. 2013, 14(1), 30-45; https://doi.org/10.3390/ijms14010030 - 20 Dec 2012

Cited by 6 | Viewed by 6505

Abstract

As more knowledge on molecular alterations favoring carcinogenesis and spreading of gastroenteropancreatic endocrine tumors has become available, a number of targeted agents interfering with key growth and angiogenic pathways have been explored in preclinical and clinical studies. The mTOR inhibitor Everolimus, and the [...] Read more.

As more knowledge on molecular alterations favoring carcinogenesis and spreading of gastroenteropancreatic endocrine tumors has become available, a number of targeted agents interfering with key growth and angiogenic pathways have been explored in preclinical and clinical studies. The mTOR inhibitor Everolimus, and the multi-target antiangiogenetic agent Sunitinib, have been shown to be effective and thus have been approved by the FDA for treatment of pancreatic endocrine tumors. However, there is little data on the primary resistance to targeted agents on these tumors. The goals of the present review are to elucidate the possible advantage of combined treatments in overcoming induced resistances, and to identify biomarkers able to predict clinical efficacy. Moreover, the role of interesting targets for which a strong biological rationale exists, and specific inhibitors are available, such as the Src Family Kinases and the Hedgehog Pathway, are discussed. There is now need for more preclinical studies on cell lines and animal models to provide a stronger preclinical background in this field, as well as clinical trials specifically comparing one targeted therapy with another or combining different targeted agents. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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The Implications of Cancer Stem Cells for Cancer Therapy

by Wenjing Jiang, Jianhua Peng, Yue Zhang, William C. S. Cho and Kunlin Jin

Int. J. Mol. Sci. 2012, 13(12), 16636-16657; https://doi.org/10.3390/ijms131216636 - 5 Dec 2012

Cited by 50 | Viewed by 11889

Abstract

Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Recent studies have showed that cancer stem cells (CSCs), a [...] Read more.

Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Recent studies have showed that cancer stem cells (CSCs), a small subpopulation of tumor cells, can generate bulk populations of nontumorigenic cancer cell progeny through the self-renewal and differentiation processes. As CSCs are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors, development of CSC-targeted therapeutic strategies holds new hope for improving survival and quality of life in patients with cancer. Therapeutic innovations will emerge from a better understanding of the biology and environment of CSCs, which, however, are largely unexplored. This review summarizes the characteristics, evidences and development of CSCs, as well as implications and challenges for cancer treatment. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Drug Conjugates Such as Antibody Drug Conjugates (ADCs), Immunotoxins and Immunoliposomes Challenge Daily Clinical Practice

by Wolf-Dieter Janthur, Nathan Cantoni and Christoph Mamot

Int. J. Mol. Sci. 2012, 13(12), 16020-16045; https://doi.org/10.3390/ijms131216020 - 28 Nov 2012

Cited by 42 | Viewed by 9622

Abstract

Drug conjugates have been studied extensively in preclinical in vitro and in vivo models but to date only a few compounds have progressed to the clinical setting. This situation is now changing with the publication of studies demonstrating a significant impact on clinical [...] Read more.

Drug conjugates have been studied extensively in preclinical in vitro and in vivo models but to date only a few compounds have progressed to the clinical setting. This situation is now changing with the publication of studies demonstrating a significant impact on clinical practice and highlighting the potential of this new class of targeted therapies. This review summarizes the pharmacological and molecular background of the main drug conjugation systems, namely antibody drug conjugates (ADCs), immunotoxins and immunoliposomes. All these compounds combine the specific targeting moiety of an antibody or similar construct with the efficacy of a toxic drug. The aim of this strategy is to target tumor cells specifically while sparing normal tissue, thus resulting in high efficacy and low toxicity. Recently, several strategies have been investigated in phase I clinical trials and some have entered phase III clinical development. This review provides a detailed overview of various strategies and critically discusses the most relevant achievements. Examples of the most advanced compounds include T-DM1 and brentuximab vedotin. However, additional promising strategies such as immunotoxins and immunoliposmes are already in clinical development. In summary, targeted drug delivery by drug conjugates is a new emerging class of anti-cancer therapy that may play a major role in the future. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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The Role of Vascular Endothelial Growth Factor A Polymorphisms in Breast Cancer

by Doonyapat Sa-nguanraksa and Pornchai O-charoenrat

Int. J. Mol. Sci. 2012, 13(11), 14845-14864; https://doi.org/10.3390/ijms131114845 - 13 Nov 2012

Cited by 43 | Viewed by 9447

Abstract

Breast cancer is the most common cancer in females and the leading cause of cancer death in women worldwide. Angiogenesis, the formation of new blood vessels, plays an important role in the development and progression of breast cancer. Vascular endothelial growth factor A [...] Read more.

Breast cancer is the most common cancer in females and the leading cause of cancer death in women worldwide. Angiogenesis, the formation of new blood vessels, plays an important role in the development and progression of breast cancer. Vascular endothelial growth factor A (VEGFA), the key modulator of angiogenesis, is highly expressed in cancer tissue and correlates with its more aggressive features. Polymorphisms of VEGFA alter the levels of expression and subsequently influence the susceptibility and aggressiveness of breast cancer. Assessment of VEGFA polymorphisms may be used for the identification of patients suitable for anti-VEGFA therapy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessReview

Microenvironments and Cellular Characteristics in the Micro Tumor Cords of Malignant Solid Tumors

by Chan Joo Yeom, Yoko Goto, Yuxi Zhu, Masahiro Hiraoka and Hiroshi Harada

Int. J. Mol. Sci. 2012, 13(11), 13949-13965; https://doi.org/10.3390/ijms131113949 - 29 Oct 2012

Cited by 52 | Viewed by 8820

Abstract

Because of the accelerated proliferation of cancer cells and the limited distance that molecular oxygen can diffuse from functional tumor blood vessels, there appears to be a unique histology in malignant solid tumors, conglomerates of micro tumor cords. A functional blood vessel exists [...] Read more.

Because of the accelerated proliferation of cancer cells and the limited distance that molecular oxygen can diffuse from functional tumor blood vessels, there appears to be a unique histology in malignant solid tumors, conglomerates of micro tumor cords. A functional blood vessel exists at the center of each tumor cord and is sequentially surrounded by well-oxygenated, oxygen-insufficient, and oxygen-depleted cancer cells in the shape of baumkuchen (layered). Cancer cells, by inducing the expression of various genes, adapt to the highly heterogeneous microenvironments in each layer. Accumulated evidence has suggested that not only tumor microenvironments but also cellular adaptive responses to them, influence the radioresistance of cancer cells. However, precisely how these factors affect one another and eventually influence the therapeutic effect of radiation therapy remains to be elucidated. Here, based on recent basic and clinical cancer research, we deduced extrinsic (oxygen concentration, glucose concentration, pH etc.) and intrinsic (transcriptional activity of hypoxia-inducible factor 1, metabolic pathways, cell cycle status, proliferative activity etc.) parameters in each layer of a tumor cord. In addition, we reviewed the latest information about the molecular mechanism linking these factors with both tumor radioresistance and tumor recurrence after radiation therapy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessReview

The Criteria to Confirm the Role of Epstein-Barr Virus in Nasopharyngeal Carcinoma Initiation

by Ai-Di Gu, Mu-Sheng Zeng and Chao-Nan Qian

Int. J. Mol. Sci. 2012, 13(10), 13737-13747; https://doi.org/10.3390/ijms131013737 - 23 Oct 2012

Cited by 18 | Viewed by 6780

Abstract

Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), but it remains obscure whether EBV is a viral cause of, or only an accompaniment of, NPC. We will discuss the accumulated evidence pointing to the relationship between EBV infection and NPC initiation from [...] Read more.

Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), but it remains obscure whether EBV is a viral cause of, or only an accompaniment of, NPC. We will discuss the accumulated evidence pointing to the relationship between EBV infection and NPC initiation from epidemiologic, pathogenic, molecular oncogenic, and experimental animal studies. We believe that convincing evidence from these perspectives must be provided before we can ascertain the causal role of EBV infection in NPC. Specifically, (1) epidemiological studies should reveal EBV infection as a risk factor; (2) the introduction of EBV into an animal model should produce NPC; (3) in the animal model NPC, the main molecular event(s) or the involved signaling pathway(s) should be identical to that in human NPC; and (4) finally and most importantly, prevention of EBV infection or clearance of EBV from infected individuals must be able to reduce the incidence rate of NPC. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessReview

Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities

by Yong Zhang, Peixin Jiang, Min Ye, Sung-Hoon Kim, Cheng Jiang and Junxuan Lü

Int. J. Mol. Sci. 2012, 13(10), 13621-13666; https://doi.org/10.3390/ijms131013621 - 22 Oct 2012

Cited by 208 | Viewed by 14716

Abstract

Tanshinones are a class of abietane diterpene compound isolated from Salvia miltiorrhiza (Danshen or Tanshen in Chinese), a well-known herb in Traditional Chinese Medicine (TCM). Since they were first identified in the 1930s, more than 40 lipophilic tanshinones and structurally related compounds have [...] Read more.

Tanshinones are a class of abietane diterpene compound isolated from Salvia miltiorrhiza (Danshen or Tanshen in Chinese), a well-known herb in Traditional Chinese Medicine (TCM). Since they were first identified in the 1930s, more than 40 lipophilic tanshinones and structurally related compounds have been isolated from Danshen. In recent decades, numerous studies have been conducted to investigate the isolation, identification, synthesis and pharmacology of tanshinones. In addition to the well-studied cardiovascular activities, tanshinones have been investigated more recently for their anti-cancer activities in vitro and in vivo. In this review, we update the herbal and alternative sources of tanshinones, and the pharmacokinetics of selected tanshinones. We discuss anti-cancer properties and identify critical issues for future research. Whereas previous studies have suggested anti-cancer potential of tanshinones affecting multiple cellular processes and molecular targets in cell culture models, data from in vivo potency assessment experiments in preclinical models vary greatly due to lack of uniformity of solvent vehicles and routes of administration. Chemical modifications and novel formulations had been made to address the poor oral bioavailability of tanshinones. So far, human clinical trials have been far from ideal in their design and execution for the purpose of supporting an anti-cancer indication of tanshinones. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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The Role of MicroRNAs in Breast Cancer Migration, Invasion and Metastasis

by Joy Tang, Aamir Ahmad and Fazlul H. Sarkar

Int. J. Mol. Sci. 2012, 13(10), 13414-13437; https://doi.org/10.3390/ijms131013414 - 18 Oct 2012

Cited by 166 | Viewed by 13032

Abstract

MicroRNAs (miRNAs) are a major class of small, noncoding RNA molecules that regulate gene expression by targeting mRNAs to trigger either translational repression or mRNA degradation. They have recently been more widely investigated due to their potential role as targets for cancer therapy. [...] Read more.

MicroRNAs (miRNAs) are a major class of small, noncoding RNA molecules that regulate gene expression by targeting mRNAs to trigger either translational repression or mRNA degradation. They have recently been more widely investigated due to their potential role as targets for cancer therapy. Many miRNAs have been implicated in several human cancers, including breast cancer. miRNAs are known to regulate cell cycle and development, and thus may serve as useful targets for exploration in anticancer therapeutics. The link between altered miRNA signatures and breast cancer development and metastasis can be observed either through the loss of tumor suppressor miRNAs, such as let-7s, miR-30a/31/34a/125s/200s/203/205/206/342 or the overexpression of oncogenic miRNAs, such as miR-10b/21/135a/155/221/222/224/373/520c in breast cancer cells. Some of these miRNAs have also been validated in tumor specimens of breast cancer patients, underscoring their potential roles in diagnostics, as well as targets for novel therapeutics for breast cancer. In this review article, we will provide an overview and update of our current understanding of the mode of action of several of these well characterized miRNAs in breast cancer models. Therefore, better understanding of the gene networks orchestrated by these miRNAs may help exploit the full potential of miRNAs in regards to cancer diagnosis, treatment, and therapeutics. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Open AccessReview

The Behavior of Matrix Metalloproteinases and Their Inhibitors in Colorectal Cancer

by László Herszényi, István Hritz, Gábor Lakatos, Mária Zsófia Varga and Zsolt Tulassay

Int. J. Mol. Sci. 2012, 13(10), 13240-13263; https://doi.org/10.3390/ijms131013240 - 16 Oct 2012

Cited by 131 | Viewed by 9801

Abstract

Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix components crucial for tumor growth, invasion and metastasis. MMPs are controlled by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). We and others have demonstrated that MMPs and TIMPs are [...] Read more.

Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix components crucial for tumor growth, invasion and metastasis. MMPs are controlled by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). We and others have demonstrated that MMPs and TIMPs are especially important in the process of tumor invasion, progression and the metastasis of colorectal cancer (CRC). It has been proposed that MMPs and TIMPs might play a part not only in tumor invasion and initiation of metastasis but also in carcinogenesis from colorectal adenomas. Several recent studies demonstrated that high preoperative serum or plasma MMP-2, MMP-9 and TIMP-1 antigen levels are strong predictive factors for poor prognosis in patients with CRC and their determination might be useful for identification of patients with higher risk for cancer recurrence. MMP-9 and TIMP-1 have significant potential tumor marker impact in CRC. Their diagnostic sensitivity is consistently higher than those of conventional biomarkers. The pharmacological targeting of CRC by the development of a new generation of selective inhibitors of MMPs, that is highly specific for certain MMPs, is a promising and challenging area for the future. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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The Complexities of Epidemiology and Prevention of Gastrointestinal Cancers

by Saba Haq, Shadan Ali, Ramzi Mohammad and Fazlul H. Sarkar

Int. J. Mol. Sci. 2012, 13(10), 12556-12572; https://doi.org/10.3390/ijms131012556 - 1 Oct 2012

Cited by 19 | Viewed by 6884

Abstract

Cancer epidemiology and prevention is one of the most well studied fields today. The more we can understand about the incidence and pathogenesis of this disease, the better we will be able to prevent it. Effective prevention strategies can decrease the mortality rate [...] Read more.

Cancer epidemiology and prevention is one of the most well studied fields today. The more we can understand about the incidence and pathogenesis of this disease, the better we will be able to prevent it. Effective prevention strategies can decrease the mortality rate of cancer significantly; this is why it is important to delineate the underlying causes. It has been well recognized that genetic mutations, sporadic or hereditary, may lead to increased chance of tumorigenesis. Detecting genetic mutations can lead to the identification of high-risk individuals with hereditary cancer syndromes, which may assist in devising prevention strategies. Further, environmental factors are known to play important roles in epidemiology and suggest prevention tools that could be implemented to reduce cancer incidence and subsequent cancer-associated morbidity and mortality. Chemoprevention has been tried in colon cancer and is finding new advancements in other carcinomas as well. Out of many environmental cancer preventive agents, the most notable developments are the identification of the role of vitamins E, vitamin D and folic acid. Increased consumption of these vitamins has shown to be inversely correlated with cancer risk. This review will highlight important aspects of cancer epidemiology in the most aggressive carcinomas of the gastrointestinal system focusing on colorectal adenocarcinoma and pancreatic adenocarcinoma. Additionally, some of the well-known and evolving aspects of epidemiology of colorectal and pancreatic cancer along with current and new prevention strategies will also be reviewed. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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MicroRNAs as Diagnostic Biomarkers in Gastric Cancer

by Ying Yin, Jun Li, Shujie Chen, Tianhua Zhou and Jianmin Si

Int. J. Mol. Sci. 2012, 13(10), 12544-12555; https://doi.org/10.3390/ijms131012544 - 1 Oct 2012

Cited by 39 | Viewed by 6940

Abstract

Considering the high mortality rates and the unfavorable prognosis of gastric cancer (GC) as well as the lack of a clinical predictive marker, which is sufficiently sensitive to GC, it is of great significance to investigate new sensitive and specific markers for GC [...] Read more.

Considering the high mortality rates and the unfavorable prognosis of gastric cancer (GC) as well as the lack of a clinical predictive marker, which is sufficiently sensitive to GC, it is of great significance to investigate new sensitive and specific markers for GC diagnosis. MicroRNAs (miRNAs) could be a practical form of potential biomarkers in the diagnosis of human disease, and they are confirmed to be closely associated with GC. In this review, we discuss the recent research results that indicate the feasibility and clinical applications of miRNAs in GC. Although several challenges remain to be addressed, miRNAs have the potential to be applied in the diagnosis of GC. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Phosphoproteomics and Lung Cancer Research

by Elena López and William C. S. Cho

Int. J. Mol. Sci. 2012, 13(10), 12287-12314; https://doi.org/10.3390/ijms131012287 - 26 Sep 2012

Cited by 12 | Viewed by 7863

Abstract

Massive evidence suggests that genetic abnormalities contribute to the development of lung cancer. These molecular abnormalities may serve as diagnostic, prognostic and predictive biomarkers for this deadly disease. It is imperative to search these biomarkers in different tumorigenesis pathways so as to provide [...] Read more.

Massive evidence suggests that genetic abnormalities contribute to the development of lung cancer. These molecular abnormalities may serve as diagnostic, prognostic and predictive biomarkers for this deadly disease. It is imperative to search these biomarkers in different tumorigenesis pathways so as to provide the most appropriate therapy for each individual patient with lung malignancy. Phosphoproteomics is a promising technology for the identification of biomarkers and novel therapeutic targets for cancer. Thousands of proteins interact via physical and chemical association. Moreover, some proteins can covalently modify other proteins post-translationally. These post-translational modifications ultimately give rise to the emergent functions of cells in sequence, space and time. Phosphoproteomics clinical researches imply the comprehensive analysis of the proteins that are expressed in cells or tissues and can be employed at different stages. In addition, understanding the functions of phosphorylated proteins requires the study of proteomes as linked systems rather than collections of individual protein molecules. In fact, proteomics approaches coupled with affinity chromatography strategies followed by mass spectrometry have been used to elucidate relevant biological questions. This article will discuss the relevant clues of post-translational modifications, phosphorylated proteins, and useful proteomics approaches to identify molecular cancer signatures. The recent progress in phosphoproteomics research in lung cancer will be also discussed. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Prognostic and Predictive Roles of KRAS Mutation in Colorectal Cancer

by Amanda K. Arrington, Eileen L. Heinrich, Wendy Lee, Marjun Duldulao, Supriya Patel, Julian Sanchez, Julio Garcia-Aguilar and Joseph Kim

Int. J. Mol. Sci. 2012, 13(10), 12153-12168; https://doi.org/10.3390/ijms131012153 - 25 Sep 2012

Cited by 170 | Viewed by 20018

Abstract

The RAS gene family is among the most studied and best characterized of the known cancer-related genes. Of the three human ras isoforms, KRAS is the most frequently altered gene, with mutations occurring in 17%–25% of all cancers. In particular, approximately 30%–40% of [...] Read more.

The RAS gene family is among the most studied and best characterized of the known cancer-related genes. Of the three human ras isoforms, KRAS is the most frequently altered gene, with mutations occurring in 17%–25% of all cancers. In particular, approximately 30%–40% of colon cancers harbor a KRAS mutation. KRAS mutations in colon cancers have been associated with poorer survival and increased tumor aggressiveness. Additionally, KRAS mutations in colorectal cancer lead to resistance to select treatment strategies. In this review we examine the history of KRAS, its prognostic value in patients with colorectal cancer, and evidence supporting its predictive value in determining appropriate therapies for patients with colorectal cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Personalized Targeted Therapy for Lung Cancer

by Kehua Wu, Larry House, Wanqing Liu and William C.S. Cho

Int. J. Mol. Sci. 2012, 13(9), 11471-11496; https://doi.org/10.3390/ijms130911471 - 13 Sep 2012

Cited by 60 | Viewed by 15049

Abstract

Lung cancer has long been recognized as an extremely heterogeneous disease, since its development is unique in every patient in terms of clinical characterizations, prognosis, response and tolerance to treatment. Personalized medicine refers to the use of markers to predict which patient will [...] Read more.

Lung cancer has long been recognized as an extremely heterogeneous disease, since its development is unique in every patient in terms of clinical characterizations, prognosis, response and tolerance to treatment. Personalized medicine refers to the use of markers to predict which patient will most likely benefit from a treatment. In lung cancer, the well-developed epidermal growth factor receptor (EGFR) and the newly emerging EML4-anaplastic lymphoma kinase (ALK) are important therapeutic targets. This review covers the basic mechanism of EGFR and EML4-ALK activation, the predictive biomarkers, the mechanism of resistance, and the current targeted tyrosine kinase inhibitors. The efficacy of EGFR and ALK targeted therapies will be discussed in this review by summarizing the prospective clinical trials, which were performed in biomarker-based selected patients. In addition, the revolutionary sequencing and systems strategies will also be included in this review since these technologies will provide a comprehensive understanding in the molecular characterization of cancer, allow better stratification of patients for the most appropriate targeted therapies, eventually resulting in a more promising personalized treatment. The relatively low incidence of EGFR and ALK in non-Asian patients and the lack of response in mutant patients limit the application of the therapies targeting EGFR or ALK. Nevertheless, it is foreseeable that the sequencing and systems strategies may offer a solution for those patients. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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The Dual Role of Inflammation in Colon Carcinogenesis

by Giovanni Monteleone, Francesco Pallone and Carmine Stolfi

Int. J. Mol. Sci. 2012, 13(9), 11071-11084; https://doi.org/10.3390/ijms130911071 - 6 Sep 2012

Cited by 81 | Viewed by 7917

Abstract

Chronic inflammation characterizing patients with inflammatory bowel disease (IBD) represents a major risk factor for the development of colorectal cancer. Mechanisms underlying this neoplastic transformation are not fully understood though studies in experimental models of colon carcinogenesis suggest that inflammatory cell-derived cytokines either [...] Read more.

Chronic inflammation characterizing patients with inflammatory bowel disease (IBD) represents a major risk factor for the development of colorectal cancer. Mechanisms underlying this neoplastic transformation are not fully understood though studies in experimental models of colon carcinogenesis suggest that inflammatory cell-derived cytokines either directly or indirectly stimulate the uncontrolled growth of cancer cells. Nevertheless, under specific inflammatory conditions, immune cells can boost an anti-tumor immune response with the down-stream effect of eliminating dysplastic and cancerous cells. This review outlines the beneficial and detrimental role of inflammation in colon carcinogenesis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Intravascular Targets for Molecular Contrast-Enhanced Ultrasound Imaging

by Siver A. Moestue, Ingrid S. Gribbestad and Rune Hansen

Int. J. Mol. Sci. 2012, 13(6), 6679-6697; https://doi.org/10.3390/ijms13066679 - 1 Jun 2012

Cited by 28 | Viewed by 9238

Abstract

Molecular targeting of contrast agents for ultrasound imaging is emerging as a new medical imaging modality. It combines advances in ultrasound technology with principles of molecular imaging, thereby allowing non-invasive assessment of biological processes in vivo. Preclinical studies have shown that microbubbles, [...] Read more.

Molecular targeting of contrast agents for ultrasound imaging is emerging as a new medical imaging modality. It combines advances in ultrasound technology with principles of molecular imaging, thereby allowing non-invasive assessment of biological processes in vivo. Preclinical studies have shown that microbubbles, which provide contrast during ultrasound imaging, can be targeted to specific molecular markers. These microbubbles accumulate in tissue with target (over) expression, thereby significantly increasing the ultrasound signal. This concept offers safe and low-cost imaging with high spatial resolution and sensitivity. It is therefore considered to have great potential in cancer imaging, and early-phase clinical trials are ongoing. In this review, we summarize the current literature on targets that have been successfully imaged in preclinical models using molecularly targeted ultrasound contrast agents. Based on preclinical experience, we discuss the potential clinical utility of targeted microbubbles. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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