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6526 KiB

Open AccessArticle

EIYMNVPV Motif is Essential for A1CF Nucleus Localization and A1CF (-8aa) Promotes Proliferation of MDA-MB-231 Cells via Up-Regulation of IL-6

by Li Zhou, Jin Hao, Yue Yuan, Rui Peng, Honglian Wang, Dongsheng Ni, Yuping Gu, Liyuan Huang, Zhaomin Mao, Zhongshi Lyu, Yao Du, Zhicheng Liu, Yiman Li, Pan Ju, Yaoshui Long, Jianing Liu and Qin Zhou

Int. J. Mol. Sci. 2016, 17(6), 811; https://doi.org/10.3390/ijms17060811 - 25 May 2016

Cited by 9 | Viewed by 6094

Abstract

Apobec-1 complementation factor (A1CF) is a heterogeneous nuclear ribonuceloprotein (hnRNP) and mediates apolipoprotein-B mRNA editing. A1CF can promote the regeneration of the liver by post-transcriptionally stabilizing Interleukin-6 (IL-6) mRNA. It also contains two transcriptional variants-A1CF64 and A1CF65, distinguished by the appearance [...] Read more.

Apobec-1 complementation factor (A1CF) is a heterogeneous nuclear ribonuceloprotein (hnRNP) and mediates apolipoprotein-B mRNA editing. A1CF can promote the regeneration of the liver by post-transcriptionally stabilizing Interleukin-6 (IL-6) mRNA. It also contains two transcriptional variants-A1CF64 and A1CF65, distinguished by the appearance of a 24-nucleotide motif which contributes to the corresponding eight-amino acid motif of EIYMNVPV. For the first time, we demonstrated that the EIYMNVPV motif was essential for A1CF nucleus localization, A1CF deficient of the EIYMNVPV motif, A1CF (-8aa) showed cytoplasm distribution. More importantly, we found that A1CF (-8aa), but not its full-length counterpart, can promote proliferation of MDA-MB-231 cells accompanied with increased level of IL-6 mRNA. Furthermore, silencing of IL-6 attenuated A1CF (-8aa)-induced proliferation in MDA-MB-231 cells. In conclusion, notably, these findings suggest that A1CF (-8aa) promoted proliferation of MDA-MB-231 cells in vitro viewing IL-6 as a target. Thus, the EIYMNVPV motif could be developed as a potential target for basal-like breast cancer therapy. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Open AccessArticle

Identification of Serum Peptidome Signatures of Non-Small Cell Lung Cancer

by Agnieszka Klupczynska, Agata Swiatly, Joanna Hajduk, Jan Matysiak, Wojciech Dyszkiewicz, Krystian Pawlak and Zenon J. Kokot

Int. J. Mol. Sci. 2016, 17(4), 410; https://doi.org/10.3390/ijms17040410 - 31 Mar 2016

Cited by 19 | Viewed by 6305

Abstract

Due to high mortality rates of lung cancer, there is a need for identification of new, clinically useful markers, which improve detection of this tumor in early stage of disease. In the current study, serum peptide profiling was evaluated as a diagnostic tool [...] Read more.

Due to high mortality rates of lung cancer, there is a need for identification of new, clinically useful markers, which improve detection of this tumor in early stage of disease. In the current study, serum peptide profiling was evaluated as a diagnostic tool for non-small cell lung cancer patients. The combination of the ZipTip technology with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) for the analysis of peptide pattern of cancer patients (n = 153) and control subjects (n = 63) was presented for the first time. Based on the observed significant differences between cancer patients and control subjects, the classification model was created, which allowed for accurate group discrimination. The model turned out to be robust enough to discriminate a new validation set of samples with satisfactory sensitivity and specificity. Two peptides from the diagnostic pattern for non-small cell lung cancer (NSCLC) were identified as fragments of C3 and fibrinogen α chain. Since ELISA test did not confirm significant differences in the expression of complement component C3, further study will involve a quantitative approach to prove clinical utility of the other proteins from the proposed multi-peptide cancer signature. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Open AccessArticle

Alisertib Induces Cell Cycle Arrest, Apoptosis, Autophagy and Suppresses EMT in HT29 and Caco-2 Cells

by Bao-Jun Ren, Zhi-Wei Zhou, Da-Jian Zhu, Yong-Le Ju, Jin-Hao Wu, Man-Zhao Ouyang, Xiao-Wu Chen and Shu-Feng Zhou

Int. J. Mol. Sci. 2016, 17(1), 41; https://doi.org/10.3390/ijms17010041 - 29 Dec 2015

Cited by 36 | Viewed by 15342

Abstract

Colorectal cancer (CRC) is one of the most common malignancies worldwide with substantial mortality and morbidity. Alisertib (ALS) is a selective Aurora kinase A (AURKA) inhibitor with unclear effect and molecular interactome on CRC. This study aimed to evaluate the molecular interactome and [...] Read more.

Colorectal cancer (CRC) is one of the most common malignancies worldwide with substantial mortality and morbidity. Alisertib (ALS) is a selective Aurora kinase A (AURKA) inhibitor with unclear effect and molecular interactome on CRC. This study aimed to evaluate the molecular interactome and anticancer effect of ALS and explore the underlying mechanisms in HT29 and Caco-2 cells. ALS markedly arrested cells in G₂/M phase in both cell lines, accompanied by remarkable alterations in the expression level of key cell cycle regulators. ALS induced apoptosis in HT29 and Caco-2 cells through mitochondrial and death receptor pathways. ALS also induced autophagy in HT29 and Caco-2 cells, with the suppression of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), but activation of 5′ AMP-activated protein kinase (AMPK) signaling pathways. There was a differential modulating effect of ALS on p38 MAPK signaling pathway in both cell lines. Moreover, induction or inhibition of autophagy modulated basal and ALS-induced apoptosis in both cell lines. ALS potently suppressed epithelial to mesenchymal transition (EMT) in HT29 and Caco-2 cells. Collectively, it suggests that induction of cell cycle arrest, promotion of apoptosis and autophagy, and suppression of EMT involving mitochondrial, death receptor, PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways contribute to the cancer cell killing effect of ALS on CRC cells. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Open AccessArticle

CHMP4C Disruption Sensitizes the Human Lung Cancer Cells to Irradiation

by Kang Li, Jianxiang Liu, Mei Tian, Gang Gao, Xuesong Qi, Yan Pan, Jianlei Ruan, Chunxu Liu and Xu Su

Int. J. Mol. Sci. 2016, 17(1), 18; https://doi.org/10.3390/ijms17010018 - 24 Dec 2015

Cited by 20 | Viewed by 7461

Abstract

Human lung cancer is highly invasive and the most malignant among human tumors. Adenocarcinoma as a specific type of non-small cell lung cancer occurs with high frequency and is also highly resistant to radiation therapy. Thus, how to avoid radiation resistance and improve [...] Read more.

Human lung cancer is highly invasive and the most malignant among human tumors. Adenocarcinoma as a specific type of non-small cell lung cancer occurs with high frequency and is also highly resistant to radiation therapy. Thus, how to avoid radiation resistance and improve radiotherapy effectiveness is a crucial question. In the present study, human lung cancer A549 and H1299 cells were irradiated using γ-rays from a Co60 irradiator. Protein expression was detected by Western blotting. Cell cycle and apoptosis were measured by flow cytometry. Surviving fraction was determined by colony formation assay. γH2AX and 53BP1 foci formation were examined by fluorescence microscopy. In the results, we show that CHMP4C, a subunit of Endosomal sorting complex-III (ESCRT-III), is involved in radiation-induced cellular response. Radiation-induced Aurora B expression enhances CHMP4C phosphorylation in non-small cell lung cancer (NSCLC) cells, maintaining cell cycle check-point and cellular viability as well as resisting apoptosis. CHMP4C depletion enhances cellular sensitivity to radiation, delays S-phase of cell cycle and reduces ionizing radiation (IR)-induced γH2AX foci formation. We found that Aurora B targets CHMP4C and inhibition of Aurora B exhibits similar effects with silencing of CHMP4C in radioresistance. We also confirm that CHMP4C phosphorylation is elevated after IR both in p53-positive and-negative cells, indicating that the close correlation between CHMP4C and Aurora B signaling pathway in mediating radiation resistance is not p53 dependent. Together, our work establishes a new function of CHMP4C in radiation resistance, which will offer a potential strategy for non-small cell lung cancer by disrupting CHMP4C. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Open AccessArticle

Fulvic Acid Attenuates Resistin-Induced Adhesion of HCT-116 Colorectal Cancer Cells to Endothelial Cells

by Wen-Shih Huang, Jen-Tsung Yang, Chien-Chang Lu, Shun-Fu Chang, Cheng-Nan Chen, Yu-Ping Su and Ko-Chao Lee

Int. J. Mol. Sci. 2015, 16(12), 29370-29382; https://doi.org/10.3390/ijms161226174 - 9 Dec 2015

Cited by 18 | Viewed by 6588

Abstract

A high level of serum resistin has recently been found in patients with a number of cancers, including colorectal cancer (CRC). Hence, resistin may play a role in CRC development. Fulvic acid (FA), a class of humic substances, possesses pharmacological properties. However, the [...] Read more.

A high level of serum resistin has recently been found in patients with a number of cancers, including colorectal cancer (CRC). Hence, resistin may play a role in CRC development. Fulvic acid (FA), a class of humic substances, possesses pharmacological properties. However, the effect of FA on cancer pathophysiology remains unclear. The aim of this study was to investigate the effect of resistin on the endothelial adhesion of CRC and to determine whether FA elicits an antagonistic mechanism to neutralize this resistin effect. Human HCT-116 (p53-negative) and SW-48 (p53-positive) CRC cells and human umbilical vein endothelial cells (HUVECs) were used in the experiments. Treatment of both HCT-116 and SW-48 cells with resistin increases the adhesion of both cells to HUVECs. This result indicated that p53 may not regulate this resistin effect. A mechanistic study in HCT-116 cells further showed that this resistin effect occurs via the activation of NF-κB and the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Co-treating cells with both FA and resistin revealed that FA significantly attenuated the resistin-increased NF-κB activation and ICAM-1/VCAM-1 expression and the consequent adhesion of HCT-116 cells to HUVECs. These results demonstrate the role of resistin in promoting HCT-116 cell adhesion to HUVECs and indicate that FA might be a potential candidate for the inhibition of the endothelial adhesion of CRC in response to resistin. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Open AccessArticle

Next-Generation Sequencing Workflow for NSCLC Critical Samples Using a Targeted Sequencing Approach by Ion Torrent PGM™ Platform

by Irene Vanni, Simona Coco, Anna Truini, Marta Rusmini, Maria Giovanna Dal Bello, Angela Alama, Barbara Banelli, Marco Mora, Erika Rijavec, Giulia Barletta, Carlo Genova, Federica Biello, Claudia Maggioni and Francesco Grossi

Int. J. Mol. Sci. 2015, 16(12), 28765-28782; https://doi.org/10.3390/ijms161226129 - 3 Dec 2015

Cited by 34 | Viewed by 12306

Abstract

Next-generation sequencing (NGS) is a cost-effective technology capable of screening several genes simultaneously; however, its application in a clinical context requires an established workflow to acquire reliable sequencing results. Here, we report an optimized NGS workflow analyzing 22 lung cancer-related genes to sequence [...] Read more.

Next-generation sequencing (NGS) is a cost-effective technology capable of screening several genes simultaneously; however, its application in a clinical context requires an established workflow to acquire reliable sequencing results. Here, we report an optimized NGS workflow analyzing 22 lung cancer-related genes to sequence critical samples such as DNA from formalin-fixed paraffin-embedded (FFPE) blocks and circulating free DNA (cfDNA). Snap frozen and matched FFPE gDNA from 12 non-small cell lung cancer (NSCLC) patients, whose gDNA fragmentation status was previously evaluated using a multiplex PCR-based quality control, were successfully sequenced with Ion Torrent PGM™. The robust bioinformatic pipeline allowed us to correctly call both Single Nucleotide Variants (SNVs) and indels with a detection limit of 5%, achieving 100% specificity and 96% sensitivity. This workflow was also validated in 13 FFPE NSCLC biopsies. Furthermore, a specific protocol for low input gDNA capable of producing good sequencing data with high coverage, high uniformity, and a low error rate was also optimized. In conclusion, we demonstrate the feasibility of obtaining gDNA from FFPE samples suitable for NGS by performing appropriate quality controls. The optimized workflow, capable of screening low input gDNA, highlights NGS as a potential tool in the detection, disease monitoring, and treatment of NSCLC. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Overexpression of X-Box Binding Protein 1 (XBP1) Correlates to Poor Prognosis and Up-Regulation of PI3K/mTOR in Human Osteosarcoma

by Jielai Yang, Dongdong Cheng, Shumin Zhou, Bin Zhu, Tu Hu and Qingcheng Yang

Int. J. Mol. Sci. 2015, 16(12), 28635-28646; https://doi.org/10.3390/ijms161226123 - 2 Dec 2015

Cited by 38 | Viewed by 7754

Abstract

Increasing evidence demonstrates that dysregulation of XBP1 function contributes to tumorigenesis in some cancers. However, little is known about the role of XBP1 in the progression of osteosarcoma (OS). The expression of XBP1 in OS samples was measured by quantitative RT-PCR and Western [...] Read more.

Increasing evidence demonstrates that dysregulation of XBP1 function contributes to tumorigenesis in some cancers. However, little is known about the role of XBP1 in the progression of osteosarcoma (OS). The expression of XBP1 in OS samples was measured by quantitative RT-PCR and Western blotting assays. Cell cycle analysis and cell counting kit 8 (CCK8) assays were performed to determine the effects of XBP1 expression on cells growth capacity. Cell apoptosis coassay was applied to determine cell survival. The expression of genes affected by XBP1 was examined by quantitative RT-RCR and validated by Western blotting assays. XBP1 was overexpressed in OS clinical samples compared with corresponding non-cancerous tissues. Overexpression of XBP1 was significantly associated with advanced clinical stages, high degree of malignancy and low tumor necrosis rate. Furthermore, hypoxia activated XBP1, and silencing XBP1 significantly enhanced OS cell apoptosis. Knock-down of XBP1 resulted in inhibition of OS growth. Most importantly, knockdown of XBP1 led to down-regulation of PIK3R3 and mTOR. Taken together, XBP1 is up-regulated and has a pro-tumor effect in OS with activation of PI3K/mTOR signaling. Thus, targeting XBP1 may provide a new potential therapeutic method for OS. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Open AccessArticle

DAG/PKCδ and IP3/Ca²⁺/CaMK IIβ Operate in Parallel to Each Other in PLCγ1-Driven Cell Proliferation and Migration of Human Gastric Adenocarcinoma Cells, through Akt/mTOR/S6 Pathway

by Lianzhi Dai, Luhua Zhuang, Bingchang Zhang, Fen Wang, Xiaolei Chen, Chun Xia and Bing Zhang

Int. J. Mol. Sci. 2015, 16(12), 28510-28522; https://doi.org/10.3390/ijms161226116 - 1 Dec 2015

Cited by 27 | Viewed by 7685

Abstract

Phosphoinositide specific phospholipase Cγ (PLCγ) activates diacylglycerol (DAG)/protein kinase C (PKC) and inositol 1,4,5-trisphosphate (IP3)/Ca²⁺/calmodulin-dependent protein kinase II (CaMK II) axes to regulate import events in some cancer cells, including gastric adenocarcinoma cells. However, whether DAG/PKCδ and IP3/Ca²⁺/CaMK IIβ [...] Read more.

Phosphoinositide specific phospholipase Cγ (PLCγ) activates diacylglycerol (DAG)/protein kinase C (PKC) and inositol 1,4,5-trisphosphate (IP3)/Ca²⁺/calmodulin-dependent protein kinase II (CaMK II) axes to regulate import events in some cancer cells, including gastric adenocarcinoma cells. However, whether DAG/PKCδ and IP3/Ca²⁺/CaMK IIβ axes are simultaneously involved in PLCγ1-driven cell proliferation and migration of human gastric adenocarcinoma cells and the underlying mechanism are not elucidated. Here, we investigated the role of DAG/PKCδ or CaMK IIβ in PLCγ1-driven cell proliferation and migration of human gastric adenocarcinoma cells, using the BGC-823 cell line. The results indicated that the inhibition of PKCδ and CaMK IIβ could block cell proliferation and migration of BGC-823 cells as well as the effect of inhibiting PLCγ1, including the decrease of cell viability, the increase of apoptotic index, the down-regulation of matrix metalloproteinase (MMP) 9 expression level, and the decrease of cell migration rate. Both DAG/PKCδ and CaMK IIβ triggered protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/S6 pathway to regulate protein synthesis. The data indicate that DAG/PKCδ and IP3/Ca²⁺/CaMK IIβ operate in parallel to each other in PLCγ1-driven cell proliferation and migration of human gastric adenocarcinoma cells through Akt/mTOR/S6 pathway, with important implication for validating PLCγ1 as a molecular biomarker in early gastric cancer diagnosis and disease surveillance. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Open AccessArticle

High SPARC Expression Starting from Dysplasia, Associated with Breast Carcinoma, Is Predictive for Bone Metastasis without Enhancement of Plasma Levels

by Paola Maroni, Paola Bendinelli, Daniele Morelli, Lorenzo Drago, Alessandro Luzzati, Giuseppe Perrucchini, Chiara Bonini, Emanuela Matteucci and Maria Alfonsina Desiderio

Int. J. Mol. Sci. 2015, 16(12), 28108-28122; https://doi.org/10.3390/ijms161225997 - 26 Nov 2015

Cited by 13 | Viewed by 5769

Abstract

In order to become established in the skeleton, metastatic cells disseminating from the breast carcinoma need to acquire organ-specific traits. There are no effective predictors for who will develop bone metastasis to guide long-term predictive therapy. Our purpose was to individuate events critical [...] Read more.

In order to become established in the skeleton, metastatic cells disseminating from the breast carcinoma need to acquire organ-specific traits. There are no effective predictors for who will develop bone metastasis to guide long-term predictive therapy. Our purpose was to individuate events critical for bone colonization to make a molecular classification of breast carcinoma useful for bone-metastasis outcome. In dysplasia adjacent to carcinoma and in pair-matched specimens of bone metastasis we examined SPARC expression and localization as well as Endothelin 1/ET_AR signals by immunohistochemistry, and the evaluation of plasma levels of SPARC by ELISA was also performed. In patients with breast carcinoma metastasizing to bone, SPARC and Endothelin 1/ET_AR axis were highly expressed from dysplasia until bone metastasis, but the SPARC plasma level was as low as that of normal women, in contrast to patients that never develop bone metastasis, suggesting that circulating SPARC was counter adhesive. Altogether, the early identification of SPARC/Endothelin 1/ET_AR in dysplastic lesions would be important to devise therapies preventing metastasis engraftment, since often carcinoma cells spread to distant organs at the time or even before patients present with cancer. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Open AccessArticle

Danusertib Induces Apoptosis, Cell Cycle Arrest, and Autophagy but Inhibits Epithelial to Mesenchymal Transition Involving PI3K/Akt/mTOR Signaling Pathway in Human Ovarian Cancer Cells

by Dan Zi, Zhi-Wei Zhou, Ying-Jie Yang, Lin Huang, Zun-Lun Zhou, Shu-Ming He, Zhi-Xu He and Shu-Feng Zhou

Int. J. Mol. Sci. 2015, 16(11), 27228-27251; https://doi.org/10.3390/ijms161126018 - 13 Nov 2015

Cited by 47 | Viewed by 10219

Abstract

Ovarian carcinoma (OC) is one of the most common gynecological malignancies, with a poor prognosis for patients at advanced stage. Danusertib (Danu) is a pan-inhibitor of the Aurora kinases with unclear anticancer effect and underlying mechanisms in OC treatment. This study aimed to [...] Read more.

Ovarian carcinoma (OC) is one of the most common gynecological malignancies, with a poor prognosis for patients at advanced stage. Danusertib (Danu) is a pan-inhibitor of the Aurora kinases with unclear anticancer effect and underlying mechanisms in OC treatment. This study aimed to examine the cancer cell killing effect and explore the possible mechanisms with a focus on proliferation, cell cycle progression, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT) in human OC cell lines C13 and A2780cp. The results showed that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both cell lines. Danu arrested cells in G₂/M phase and led to an accumulation of polyploidy through the regulation of the expression key cell cycle modulators. Danu induced mitochondria-dependent apoptosis and autophagy in dose and time-dependent manners. Danu suppressed PI3K/Akt/mTOR signaling pathway, evident from the marked reduction in the phosphorylation of PI3K/Akt/mTOR, contributing to the autophagy inducing effect of Danu in both cell lines. In addition, Danu inhibited EMT. In aggregate, Danu exerts potent inducing effect on cell cycle arrest, apoptosis, and autophagy, but exhibits a marked inhibitory effect on EMT. PI3K/Akt/mTOR signaling pathway contributes, partially, to the cancer cell killing effect of Danu in C13 and A2780cp cells. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Elevated STAT3 Signaling-Mediated Upregulation of MMP-2/9 Confers Enhanced Invasion Ability in Multidrug-Resistant Breast Cancer Cells

by Fei Zhang, Zhiyong Wang, Yanling Fan, Qiao Xu, Wei Ji, Ran Tian and Ruifang Niu

Int. J. Mol. Sci. 2015, 16(10), 24772-24790; https://doi.org/10.3390/ijms161024772 - 16 Oct 2015

Cited by 48 | Viewed by 10865

Abstract

The development of multidrug resistance greatly impedes effective cancer therapy. Recent advances in cancer research have demonstrated that acquisition of multidrug resistance by cancer cells is usually accompanied by enhanced cell invasiveness. Several lines of evidence indicated that cross activation of other signaling [...] Read more.

The development of multidrug resistance greatly impedes effective cancer therapy. Recent advances in cancer research have demonstrated that acquisition of multidrug resistance by cancer cells is usually accompanied by enhanced cell invasiveness. Several lines of evidence indicated that cross activation of other signaling pathways during development of drug resistance may increase invasive potential of multidrug-resistant (MDR) cancer cells. However, the accurate mechanism of this process is largely undefined. In this study, to better understand the associated molecular pathways responsible for cancer progression induced by drug resistance, a MDR human breast cancer cell line SK-BR-3/EPR with P-glycoprotein overexpression was established using stepwise long-term exposure to increasing concentration of epirubicin. The SK-BR-3/EPR cell line exhibited decreased cell proliferative activity, but enhanced cell invasive capacity. We showed that the expression of metastasis-related matrix metalloproteinase (MMP)-2/9 was elevated in SK-BR-3/EPR cells. Moreover, SK-BR-3/EPR cells showed elevated activation of STAT3. Activation of STAT3 signaling is responsible for enhanced invasiveness of SK-BR-3/EPR cells through upregulation of MMP-2/9. STAT3 is a well-known oncogene and is frequently implicated in tumorigenesis and chemotherapeutic resistance. Our findings augment insight into the mechanism underlying the functional association between MDR and cancer invasiveness. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Open AccessArticle

SOCS3 Methylation Predicts a Poor Prognosis in HBV Infection-Related Hepatocellular Carcinoma

by Xin Zhang, Qingshan You, Xiaolei Zhang and Xiangmei Chen

Int. J. Mol. Sci. 2015, 16(9), 22662-22675; https://doi.org/10.3390/ijms160922662 - 18 Sep 2015

Cited by 26 | Viewed by 5513

Abstract

Suppressor of cytokine signaling 3 (SOCS3) plays crucial roles in JAK/STAT signaling pathway inhibition in hepatocellular carcinoma (HCC). However, the methylation status of SOCS3 in HBV infection-related HCC and the relationship between SOCS3 methylation and the clinical outcome remain unknown. Here, [...] Read more.

Suppressor of cytokine signaling 3 (SOCS3) plays crucial roles in JAK/STAT signaling pathway inhibition in hepatocellular carcinoma (HCC). However, the methylation status of SOCS3 in HBV infection-related HCC and the relationship between SOCS3 methylation and the clinical outcome remain unknown. Here, we reported that in HCC tumor tissues, two regions of the CpG island (CGI) in the SOCS3 promoter were subjected to methylation analysis and only the region close to the translational start site of SOCS3 was hypermethylated. In HCC tumor tissues, SOCS3 showed an increased methylation frequency and intensity compared with that in the adjacent non-tumor tissues. Moreover, SOCS3 expression was significantly down-regulated in HCC cell lines and tumor tissues, and this was inversely correlated with methylation. Kaplan–Meier curve analysis revealed that in patients with an hepatitis B virus (HBV) infection background, SOCS3 hypermethylation was significantly correlated with a poor clinical outcome of HCC patients. Our findings indicated that SOCS3 hypermethylation has already happened in non-tumor tissues and increased in both frequency and intensity in tumor tissues. This suggests that the methylation of SOCS3 could predict a poor prognosis in HBV infection-related HCC patients. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Open AccessArticle

Preliminary Evidence on the Diagnostic and Molecular Role of Circulating Soluble EGFR in Non-Small Cell Lung Cancer

by Filippo Lococo, Massimiliano Paci, Cristian Rapicetta, Teresa Rossi, Valentina Sancisi, Luca Braglia, Silvio Cavuto, Alessandra Bisagni, Italia Bongarzone, Douglas M. Noonan, Adriana Albini and Sally Maramotti

Int. J. Mol. Sci. 2015, 16(8), 19612-19630; https://doi.org/10.3390/ijms160819612 - 19 Aug 2015

Cited by 21 | Viewed by 6677

Abstract

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While [...] Read more.

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While the EGFR transmembrane form has been extensively investigated in large clinical trials, the soluble, circulating EGFR isoform (sEGFR), which may have a potential clinical use, has rarely been considered. This study investigates the use of sEGFR as a potential diagnostic biomarker for NSCLC and also characterizes the biological function of sEGFR to clarify the molecular mechanisms involved in the course of action of this protein. Plasma sEGFR levels from a heterogeneous cohort of 37 non-advanced NSCLC patients and 54 healthy subjects were analyzed by using an enzyme-linked immunosorbent assay. The biological function of sEGFR was analyzed in vitro using NSCLC cell lines, investigating effects on cell proliferation and migration. We found that plasma sEGFR was significantly decreased in the NSCLC patient group as compared to the control group (median value: 48.6 vs. 55.6 ng/mL respectively; p = 0.0002). Moreover, we demonstrated that sEGFR inhibits growth and migration of NSCLC cells in vitro through molecular mechanisms that included perturbation of EGF/EGFR cell signaling and holoreceptor internalization. These data show that sEGFR is a potential circulating biomarker with a physiological protective role, providing a first approach to the functional role of the soluble isoform of EGFR. However, the impact of these data on daily clinical practice needs to be further investigated in larger prospective studies. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Wnt3a Promotes the Vasculogenic Mimicry Formation of Colon Cancer via Wnt/β-Catenin Signaling

by Lisha Qi, Wangzhao Song, Zhiyong Liu, Xiulan Zhao, Wenfeng Cao and Baocun Sun

Int. J. Mol. Sci. 2015, 16(8), 18564-18579; https://doi.org/10.3390/ijms160818564 - 10 Aug 2015

Cited by 59 | Viewed by 8169

Abstract

Our previous study provided evidence that non-canonical Wnt signaling is involved in regulating vasculogenic mimicry (VM) formation. However, the functions of canonical Wnt signaling in VM formation have not yet been explored. In this study, we found the presence of VM was related [...] Read more.

Our previous study provided evidence that non-canonical Wnt signaling is involved in regulating vasculogenic mimicry (VM) formation. However, the functions of canonical Wnt signaling in VM formation have not yet been explored. In this study, we found the presence of VM was related to colon cancer histological differentiation (p < 0.001), the clinical stage (p < 0.001), and presence of metastasis and recurrence (p < 0.001). VM-positive colon cancer samples showed increased Wnt3a expression (p < 0.001) and β-catenin nuclear expression (p < 0.001) compared with the VM-negative samples. In vitro, over-regulated Wnt3a expression in HT29 colon cancer cells promoted the capacity to form tube-like structures in the three-dimensional (3-D) culture together with increased expression of endothelial phenotype-associated proteins such as VEGFR2 and VE-cadherin. The mouse xenograft model showed that Wnt3a-overexpressing cells grew into larger tumor masses and formed more VM than the control cells. In addition, the Wnt/β-catenin signaling antagonist Dickkopf-1(Dkk1) can reverse the capacity to form tube-like structures and can decrease the expressions of VEGFR2 and VE-cadherin in Wnt3a-overexpressing cells. Taken together, our results suggest that Wnt/β-catenin signaling is involved in VM formation in colon cancer and might contribute to the development of more accurate treatment modalities aimed at VM. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Open AccessArticle

Prognostic Value of Preoperative Serum Levels of Periostin (PN) in Early Breast Cancer (BCa)

by Pier Vitale Nuzzo, Alessandra Rubagotti, Francesca Argellati, Antonio Di Meglio, Elisa Zanardi, Linda Zinoli, Paola Comite, Michele Mussap and Francesco Boccardo

Int. J. Mol. Sci. 2015, 16(8), 17181-17192; https://doi.org/10.3390/ijms160817181 - 28 Jul 2015

Cited by 25 | Viewed by 6257

Abstract

PN is a secreted cell adhesion protein critical for carcinogenesis. Elevated serum levels of PN have been implicated as playing an important role in different types of cancer, and a few reports suggest a potential role as a prognostic marker. We evaluated the [...] Read more.

PN is a secreted cell adhesion protein critical for carcinogenesis. Elevated serum levels of PN have been implicated as playing an important role in different types of cancer, and a few reports suggest a potential role as a prognostic marker. We evaluated the prognostic significance of preoperative serum PN concentration in patients with BCa receiving curative surgery. Enzyme-Linked Immunosorbent Assay (ELISA) was performed to determine the preoperative serum PN level in 182 patients. The correlations between serum PN concentration with clinical pathological features and PN expression in primary tumor samples were analyzed. The prognostic impact of serum PN levels with all-cause and BCa-specific mortality was also investigated. Appropriate statistics were used. Elevated serum PN levels were significantly associated with patient age (p = 0.005), adjuvant systemic therapy (p = 0.04) and progesterone receptor (PgR) status (p = 0.02). No correlation between PN preoperative serum levels and other clinical-pathological parameters, including either the epithelial or the stromal PN expression of primary tumor or the combination of the two, was found. Similarly, no association between serum PN levels and either all-cause or BCa-specific mortality was found. However, subgroup analysis revealed a correlation between higher PN serum levels and all-cause mortality in patients with node-negative disease (p = 0.05) and in those with a low PgR expression (p = 0.03). Higher levels of serum PN were also found to correlate with BCa-specific mortality in the subgroup of patients who did not receive any adjuvant systemic therapy (p = 0.04). Our findings suggest that PN was detectable in the serum of early BCa patients before surgery and increased base-line serum levels predicted worse long-term survival outcomes in specific subgroups of patients. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Sinulariolide Suppresses Human Hepatocellular Carcinoma Cell Migration and Invasion by Inhibiting Matrix Metalloproteinase-2/-9 through MAPKs and PI3K/Akt Signaling Pathways

by Yu-Jen Wu, Choo-Aun Neoh, Chia-Yu Tsao, Jui-Hsin Su and Hsing-Hui Li

Int. J. Mol. Sci. 2015, 16(7), 16469-16482; https://doi.org/10.3390/ijms160716469 - 20 Jul 2015

Cited by 77 | Viewed by 14590

Abstract

Sinulariolide is an active compound isolated from the cultured soft coral Sinularia flexibilis. In this study, we investigate the migration and invasion effects of sinulariolide in hepatocellular carcinoma cell HA22T. Sinulariolide inhibited the migration and invasion effects of hepatocellular carcinoma cells in [...] Read more.

Sinulariolide is an active compound isolated from the cultured soft coral Sinularia flexibilis. In this study, we investigate the migration and invasion effects of sinulariolide in hepatocellular carcinoma cell HA22T. Sinulariolide inhibited the migration and invasion effects of hepatocellular carcinoma cells in a concentration-dependent manner. The results of zymography assay showed that sinulariolide suppressed the activities of matrix metalloproteinase (MMP)-2 and MMP-9. Moreover, protein levels of MMP-2, MMP-9, and urokinase-type plasminogen activator (uPA) were reduced by sinulariolide in a concentration-dependent manner. Sinulariolide also exerted an inhibitory effect on phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases (ERK), phosphatidylinositol 3-kinase (PI3K), Akt, Focal adhesion kinase (FAK), growth factor receptor-bound protein 2 (GRB2). Taken together, these results demonstrated that sinulariolide could inhibit hepatocellular carcinoma cell migration and invasion and alter HA22T cell metastasis by reduction of MMP-2, MMP-9, and uPA expression through the suppression of MAPKs, PI3K/Akt, and the FAK/GRB2 signaling pathway. These findings suggest that sinulariolide merits further evaluation as a chemotherapeutic agent for human hepatocellular carcinoma. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Deregulated SLC2A1 Promotes Tumor Cell Proliferation and Metastasis in Gastric Cancer

by Shiyan Yan, Yuqin Wang, Meimei Chen, Guangming Li and Jiangao Fan

Int. J. Mol. Sci. 2015, 16(7), 16144-16157; https://doi.org/10.3390/ijms160716144 - 16 Jul 2015

Cited by 42 | Viewed by 6986

Abstract

Gastric cancer (GC) is one of the common reasons of cancer-related death with few biomarkers for diagnosis and prognosis. Solute carrier family 2 (facilitated glucose transporter) member 1 protein SLC2A1, also known as glucose transporter type 1 (GLUT1), has been associated with tumor [...] Read more.

Gastric cancer (GC) is one of the common reasons of cancer-related death with few biomarkers for diagnosis and prognosis. Solute carrier family 2 (facilitated glucose transporter) member 1 protein SLC2A1, also known as glucose transporter type 1 (GLUT1), has been associated with tumor progression, metastasis, and poor prognosis in many human solid tumors. However, little is reported about its clinical significance and biological functions in GC. Here we observed a strong up-regulation of SLC2A1 in patients with GC and found that SLC2A1 was significantly correlated with depth of invasion and clinical stage. Additionally, over-expression of SLC2A1 in GC cells promotes cellular proliferation and metastasis in vitro and enhances tumor growth in vivo as well as enhancement of glucose utilization. Meanwhile, elevated SLC2A1 also contributes to tumor metastasis in vitro. Our results indicate SLC2A1 exhibits a pivotal role in tumor growth, metastasis and glucose metabolism, and also suggest SLC2A1 as a promising target for gastric cancer therapy. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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DDX3X Biomarker Correlates with Poor Survival in Human Gliomas

by Dueng-Yuan Hueng, Wen-Chiuan Tsai, Hsin-Ying Clair Chiou, Shao-Wei Feng, Chin Lin, Yao-Feng Li, Li-Chun Huang and Ming-Hong Lin

Int. J. Mol. Sci. 2015, 16(7), 15578-15591; https://doi.org/10.3390/ijms160715578 - 9 Jul 2015

Cited by 33 | Viewed by 7009

Abstract

Primary high-grade gliomas possess invasive growth and lead to unfavorable survival outcome. The investigation of biomarkers for prediction of survival outcome in patients with gliomas is important for clinical assessment. The DEAD (Asp-Glu-Ala-Asp) box helicase 3, X-linked (DDX3X) controls tumor migration, proliferation, and [...] Read more.

Primary high-grade gliomas possess invasive growth and lead to unfavorable survival outcome. The investigation of biomarkers for prediction of survival outcome in patients with gliomas is important for clinical assessment. The DEAD (Asp-Glu-Ala-Asp) box helicase 3, X-linked (DDX3X) controls tumor migration, proliferation, and progression. However, the role of DDX3X in defining the pathological grading and survival outcome in patients with human gliomas is not yet clarified. We analyzed the DDX3X gene expression, WHO pathological grading, and overall survival from de-linked data. Further validation was done using quantitative RT-PCR of cDNA from normal brain and glioma, and immunohistochemical (IHC) staining of tissue microarray. Statistical analysis of GEO datasets showed that DDX3X mRNA expression demonstrated statistically higher in WHO grade IV (n = 81) than in non-tumor controls (n = 23, p = 1.13 × 10⁻¹⁰). Moreover, DDX3X level was also higher in WHO grade III (n = 19) than in non-tumor controls (p = 2.43 × 10⁻⁵). Kaplan–Meier survival analysis showed poor survival in patients with high DDX3X mRNA levels (n = 24) than in those with low DDX3X expression (n = 53) (median survival, 115 vs. 58 weeks, p = 0.0009, by log-rank test, hazard ratio: 0.3507, 95% CI: 0.1893–0.6496). Furthermore, DDX3X mRNA expression and protein production significantly increased in glioma cells compared with normal brain tissue examined by quantitative RT-PCR, and Western blot. IHC staining showed highly staining of high-grade glioma in comparison with normal brain tissue. Taken together, DDX3X expression level positively correlates with WHO pathologic grading and poor survival outcome, indicating that DDX3X is a valuable biomarker in human gliomas. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Periostin Expression and Its Prognostic Value for Colorectal Cancer

by Zewu Li, Xin Zhang, Yongmei Yang, Sanhui Yang, Zhaogang Dong, Lutao Du, Lili Wang and Chuanxin Wang

Int. J. Mol. Sci. 2015, 16(6), 12108-12118; https://doi.org/10.3390/ijms160612108 - 27 May 2015

Cited by 42 | Viewed by 6023

Abstract

Integrin is important for cell growth, invasion and metastasis, which are frequently observed in malignant tumors. The periostin (POSTN) gene encodes the ligand for integrin, one of the key focal adhesion proteins contributing to the formation of a structural link between the extracellular [...] Read more.

Integrin is important for cell growth, invasion and metastasis, which are frequently observed in malignant tumors. The periostin (POSTN) gene encodes the ligand for integrin, one of the key focal adhesion proteins contributing to the formation of a structural link between the extracellular matrix and integrins. High expression levels of the POSTN gene are correlated with numerous human malignancies. We examined POSTN protein in colorectal cancer specimens from 115 patients by strictly following up using immunohistochemistry. Cytoplasm immunohistochemical staining showed POSTN protein expression in colorectal cancers. The positive expression rate of POSTN protein (59.13%, 68/115) in colorectal cancers was significantly higher than that in adjacent normal colon mucosa (0.47%, 11/109). POSTN over-expression in colorectal cancers was positively correlated with tumor size, differentiation, lymph node metastasis, serosal invasion, clinical stage and five-year survival rates. Further analysis showed that patients with advanced stage colorectal cancer and high POSTN expression levels had lower survival rates than those with early stage colorectal cancer and low POSTN expression levels. Overall, our results showed that POSTN played an important role in the progression of colorectal cancers. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Spontaneous γH2AX Foci in Human Solid Tumor-Derived Cell Lines in Relation to p21^WAF1 and WIP1 Expression

by Razmik Mirzayans, Bonnie Andrais, April Scott, Ying W. Wang, Robert H. Weiss and David Murray

Int. J. Mol. Sci. 2015, 16(5), 11609-11628; https://doi.org/10.3390/ijms160511609 - 20 May 2015

Cited by 19 | Viewed by 9504

Abstract

Phosphorylation of H2AX on Ser139 (γH2AX) after exposure to ionizing radiation produces nuclear foci that are detectable by immunofluorescence microscopy. These so-called γH2AX foci have been adopted as quantitative markers for DNA double-strand breaks. High numbers of spontaneous γH2AX foci have also been [...] Read more.

Phosphorylation of H2AX on Ser139 (γH2AX) after exposure to ionizing radiation produces nuclear foci that are detectable by immunofluorescence microscopy. These so-called γH2AX foci have been adopted as quantitative markers for DNA double-strand breaks. High numbers of spontaneous γH2AX foci have also been reported for some human solid tumor-derived cell lines, but the molecular mechanism(s) for this response remains elusive. Here we show that cancer cells (e.g., HCT116; MCF7) that constitutively express detectable levels of p21^WAF1 (p21) exhibit low numbers of γH2AX foci (<3/nucleus), whereas p21 knockout cells (HCT116p21−/−) and constitutively low p21-expressing cells (e.g., MDA-MB-231) exhibit high numbers of foci (e.g., >50/nucleus), and that these foci are not associated with apoptosis. The majority (>95%) of cells within HCT116p21−/− and MDA-MB-231 cultures contain high levels of phosphorylated p53, which is localized in the nucleus. We further show an inverse relationship between γH2AX foci and nuclear accumulation of WIP1, an oncogenic phosphatase. Our studies suggest that: (i) p21 deficiency might provide a selective pressure for the emergence of apoptosis-resistant progeny exhibiting genomic instability, manifested as spontaneous γH2AX foci coupled with phosphorylation and nuclear accumulation of p53; and (ii) p21 might contribute to positive regulation of WIP1, resulting in dephosphorylation of γH2AX. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Frequent Epigenetic Suppression of Tumor Suppressor Gene Glutathione Peroxidase 3 by Promoter Hypermethylation and Its Clinical Implication in Clear Cell Renal Cell Carcinoma

by Qianling Liu, Jie Jin, Jianming Ying, Mengkui Sun, Yun Cui, Lian Zhang, Ben Xu, Yu Fan and Qian Zhang

Int. J. Mol. Sci. 2015, 16(5), 10636-10649; https://doi.org/10.3390/ijms160510636 - 11 May 2015

Cited by 27 | Viewed by 5977

Abstract

The goal of this study is to identify novel tumor suppressor genes silenced by promoter methylation in clear cell renal cell carcinoma (ccRCC) and discover new epigenetic biomarkers for early cancer detection. Reactive oxygen species (ROS) is a major cause of DNA damage [...] Read more.

The goal of this study is to identify novel tumor suppressor genes silenced by promoter methylation in clear cell renal cell carcinoma (ccRCC) and discover new epigenetic biomarkers for early cancer detection. Reactive oxygen species (ROS) is a major cause of DNA damage that correlates with cancer initiation and progression. Glutathione peroxidase 3 (GPX3), the only known extracellular glycosylated enzyme of GPXs, is a major scavenger of ROS. GPX3 has been identified as a tumor suppressor in many cancers. However, the role of GPX3 in ccRCC remains unclear. This study aimed to investigate its epigenetic alteration in ccRCC and possible clinicopathological association. In our study, GPX3 methylation and down-regulation were detected in 5 out of 6 ccRCC cell lines and the GPX3 mRNA and protein expression level in ccRCC tumors was significantly lower than in adjacent non-malignant renal tissues (p < 0.0001). Treatment with 5-Aza-2'-deoxycytidine restored GPX3 expression in ccRCC cells. Aberrant methylation was further detected in 77.1% (162/210) of RCC primary tumors, but only 14.6% (7/48) in adjacent non-malignant renal tissues. GPX3 methylation status was significantly associated with higher tumor nuclear grade (p = 0.014). Thus, our results showing frequent GPX3 inactivation by promoter hypermethylation in ccRCC may reveal the failure in the cellular antioxidant system in ccRCC and may be associated with renal tumorigenesis. GPX3 tumor specific methylation may serve as a biomarker for early detection and prognosis prediction of ccRCC. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Review

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Notch Signaling in Pancreatic Development

by Xu-Yan Li, Wen-Jun Zhai and Chun-Bo Teng

Int. J. Mol. Sci. 2016, 17(1), 48; https://doi.org/10.3390/ijms17010048 - 30 Dec 2015

Cited by 55 | Viewed by 13591

Abstract

The Notch signaling pathway plays a significant role in embryonic cell fate determination and adult tissue homeostasis. Various studies have demonstrated the deep involvement of Notch signaling in the development of the pancreas and the lateral inhibition of Notch signaling in pancreatic progenitor [...] Read more.

The Notch signaling pathway plays a significant role in embryonic cell fate determination and adult tissue homeostasis. Various studies have demonstrated the deep involvement of Notch signaling in the development of the pancreas and the lateral inhibition of Notch signaling in pancreatic progenitor differentiation and maintenance. The targeted inactivation of the Notch pathway components promotes premature differentiation of the endocrine pancreas. However, there is still the contrary opinion that Notch signaling specifies the endocrine lineage. Here, we review the current knowledge of the Notch signaling pathway in pancreatic development and its crosstalk with the Wingless and INT-1 (Wnt) and fibroblast growth factor (FGF) pathways. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Targeted Radionuclide Therapy of Human Tumors

by Sergey V. Gudkov, Natalya Yu. Shilyagina, Vladimir A. Vodeneev and Andrei V. Zvyagin

Int. J. Mol. Sci. 2016, 17(1), 33; https://doi.org/10.3390/ijms17010033 - 28 Dec 2015

Cited by 150 | Viewed by 18438

Abstract

Targeted radionuclide therapy is one of the most intensively developing directions of nuclear medicine. Unlike conventional external beam therapy, the targeted radionuclide therapy causes less collateral damage to normal tissues and allows targeted drug delivery to a clinically diagnosed neoplastic malformations, as well [...] Read more.

Targeted radionuclide therapy is one of the most intensively developing directions of nuclear medicine. Unlike conventional external beam therapy, the targeted radionuclide therapy causes less collateral damage to normal tissues and allows targeted drug delivery to a clinically diagnosed neoplastic malformations, as well as metastasized cells and cellular clusters, thus providing systemic therapy of cancer. The methods of targeted radionuclide therapy are based on the use of molecular carriers of radionuclides with high affinity to antigens on the surface of tumor cells. The potential of targeted radionuclide therapy has markedly grown nowadays due to the expanded knowledge base in cancer biology, bioengineering, and radiochemistry. In this review, progress in the radionuclide therapy of hematological malignancies and approaches for treatment of solid tumors is addressed. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Prostate Cancer Stem Cells: Research Advances

by Dagmara Jaworska, Wojciech Król and Ewelina Szliszka

Int. J. Mol. Sci. 2015, 16(11), 27433-27449; https://doi.org/10.3390/ijms161126036 - 17 Nov 2015

Cited by 47 | Viewed by 9160

Abstract

Cancer stem cells have been defined as cells within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. Experimental evidence showed that these highly tumorigenic cells might be responsible for initiation [...] Read more.

Cancer stem cells have been defined as cells within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. Experimental evidence showed that these highly tumorigenic cells might be responsible for initiation and progression of cancer into invasive and metastatic disease. Eradicating prostate cancer stem cells, the root of the problem, has been considered as a promising target in prostate cancer treatment to improve the prognosis for patients with advanced stages of the disease. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Therapeutic Implications for Overcoming Radiation Resistance in Cancer Therapy

by Byeong Mo Kim, Yunkyung Hong, Seunghoon Lee, Pengda Liu, Ji Hong Lim, Yong Heon Lee, Tae Ho Lee, Kyu Tae Chang and Yonggeun Hong

Int. J. Mol. Sci. 2015, 16(11), 26880-26913; https://doi.org/10.3390/ijms161125991 - 10 Nov 2015

Cited by 182 | Viewed by 15459

Abstract

Ionizing radiation (IR), such as X-rays and gamma (γ)-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability [...] Read more.

Ionizing radiation (IR), such as X-rays and gamma (γ)-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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The Role of Autophagy in Hepatocellular Carcinoma

by Yoo Jin Lee and Byoung Kuk Jang

Int. J. Mol. Sci. 2015, 16(11), 26629-26643; https://doi.org/10.3390/ijms161125984 - 6 Nov 2015

Cited by 86 | Viewed by 8767

Abstract

Autophagy is a catabolic process involved in cellular homeostasis under basal and stressed conditions. Autophagy is crucial for normal liver physiology and the pathogenesis of liver diseases. During the last decade, the function of autophagy in hepatocellular carcinoma (HCC) has been evaluated extensively. [...] Read more.

Autophagy is a catabolic process involved in cellular homeostasis under basal and stressed conditions. Autophagy is crucial for normal liver physiology and the pathogenesis of liver diseases. During the last decade, the function of autophagy in hepatocellular carcinoma (HCC) has been evaluated extensively. Currently, autophagy is thought to play a dual role in HCC, i.e., autophagy is involved in tumorigenesis and tumor suppression. Recent investigations of autophagy have suggested that autophagy biomarkers can facilitate HCC prognosis and the establishment of therapeutic approaches. In this review, we briefly summarize the current understanding of autophagy and discuss recent evidence for its role in HCC. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Dual Inhibition of MEK and PI3K Pathway in KRAS and BRAF Mutated Colorectal Cancers

by Sally Temraz, Deborah Mukherji and Ali Shamseddine

Int. J. Mol. Sci. 2015, 16(9), 22976-22988; https://doi.org/10.3390/ijms160922976 - 23 Sep 2015

Cited by 88 | Viewed by 12504

Abstract

Colorectal cancer (CRC) is a heterogeneous disease with multiple underlying causative genetic mutations. Genetic mutations in the phosphatidylinositol-3 kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathways are frequently implicated in CRC. Targeting the downstream substrate MEK in these mutated tumors stands [...] Read more.

Colorectal cancer (CRC) is a heterogeneous disease with multiple underlying causative genetic mutations. Genetic mutations in the phosphatidylinositol-3 kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathways are frequently implicated in CRC. Targeting the downstream substrate MEK in these mutated tumors stands out as a potential target in CRC. Several selective inhibitors of MEK have entered clinical trial evaluation; however, clinical activity with single MEK inhibitors has been rarely observed and acquired resistance seems to be inevitable. Amplification of the driving oncogene KRAS(13D), which increases signaling through the ERK1/2 pathway, upregulation of the noncanonical wingless/calcium signaling pathway (Wnt), and coexisting PIK3CA mutations have all been implicated with resistance against MEK inhibitor therapy in KRAS mutated CRC. The Wnt pathway and amplification of the oncogene have also been associated with resistance to MEK inhibitors in CRCs harboring BRAF mutations. Thus, dual targeted inhibition of MEK and PI3K pathway effectors (mTOR, PI3K, AKT, IGF-1R or PI3K/mTOR inhibitors) presents a potential strategy to overcome resistance to MEK inhibitor therapy. Many clinical trials are underway to evaluate multiple combinations of these pathway inhibitors in solid tumors. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Advances in the in Vivo Raman Spectroscopy of Malignant Skin Tumors Using Portable Instrumentation

by Nikolaos Kourkoumelis, Ioannis Balatsoukas, Violetta Moulia, Aspasia Elka, Georgios Gaitanis and Ioannis D. Bassukas

Int. J. Mol. Sci. 2015, 16(7), 14554-14570; https://doi.org/10.3390/ijms160714554 - 26 Jun 2015

Cited by 63 | Viewed by 8148

Abstract

Raman spectroscopy has emerged as a promising tool for real-time clinical diagnosis of malignant skin tumors offering a number of potential advantages: it is non-intrusive, it requires no sample preparation, and it features high chemical specificity with minimal water interference. However, in vivo [...] Read more.

Raman spectroscopy has emerged as a promising tool for real-time clinical diagnosis of malignant skin tumors offering a number of potential advantages: it is non-intrusive, it requires no sample preparation, and it features high chemical specificity with minimal water interference. However, in vivo tissue evaluation and accurate histopathological classification remain a challenging task for the successful transition from laboratory prototypes to clinical devices. In the literature, there are numerous reports on the applications of Raman spectroscopy to biomedical research and cancer diagnostics. Nevertheless, cases where real-time, portable instrumentations have been employed for the in vivo evaluation of skin lesions are scarce, despite their advantages in use as medical devices in the clinical setting. This paper reviews the advances in real-time Raman spectroscopy for the in vivo characterization of common skin lesions. The translational momentum of Raman spectroscopy towards the clinical practice is revealed by (i) assembling the technical specifications of portable systems and (ii) analyzing the spectral characteristics of in vivo measurements. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Circulating Long Noncoding RNA as a Potential Target for Prostate Cancer

by Yin-Jie Su, Jin Yu, Ya-Qin Huang and Jin Yang

Int. J. Mol. Sci. 2015, 16(6), 13322-13338; https://doi.org/10.3390/ijms160613322 - 11 Jun 2015

Cited by 44 | Viewed by 5935

Abstract

Prostate cancer is considered the second most common visceral malignancy in men in Western countries. Its emergence is largely due to the coordination of a malignant network, and long noncoding RNA has been recently demonstrated to play a critical role in prostate carcinogenesis. [...] Read more.

Prostate cancer is considered the second most common visceral malignancy in men in Western countries. Its emergence is largely due to the coordination of a malignant network, and long noncoding RNA has been recently demonstrated to play a critical role in prostate carcinogenesis. The aberrant expression of long noncoding RNA in prostate cancer patients is strongly associated with diagnosis, risk stratification and carcinogenesis, information that provides new insight into the complicated intracellular milieu of prostate cancer. This review focuses mainly on literature evidence for the role of long noncoding RNA in prostate cancer, which may suggest novel strategies for its prognosis, diagnosis and clinical treatment. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Caffeic Acid Phenethyl Ester Is a Potential Therapeutic Agent for Oral Cancer

by Ying-Yu Kuo, Wai-Tim Jim, Liang-Cheng Su, Chi-Jung Chung, Ching-Yu Lin, Chieh Huo, Jen-Chih Tseng, Shih-Han Huang, Chih-Jen Lai, Bo-Chih Chen, Bi-Juan Wang, Tzu-Min Chan, Hui-Ping Lin, Wun-Shaing Wayne Chang, Chuang-Rung Chang and Chih-Pin Chuu

Int. J. Mol. Sci. 2015, 16(5), 10748-10766; https://doi.org/10.3390/ijms160510748 - 12 May 2015

Cited by 80 | Viewed by 9690

Abstract

Head and neck cancers, which affect 650,000 people and cause 350,000 deaths per year, is the sixth leading cancer by cancer incidence and eighth by cancer-related death worldwide. Oral cancer is the most common type of head and neck cancer. More than 90% [...] Read more.

Head and neck cancers, which affect 650,000 people and cause 350,000 deaths per year, is the sixth leading cancer by cancer incidence and eighth by cancer-related death worldwide. Oral cancer is the most common type of head and neck cancer. More than 90% of oral cancers are oral and oropharyngeal squamous cell carcinoma (OSCC). The overall five-year survival rate of OSCC patients is approximately 63%, which is due to the low response rate to current therapeutic drugs. In this review we discuss the possibility of using caffeic acid phenethyl ester (CAPE) as an alternative treatment for oral cancer. CAPE is a strong antioxidant extracted from honeybee hive propolis. Recent studies indicate that CAPE treatment can effectively suppress the proliferation, survival, and metastasis of oral cancer cells. CAPE treatment inhibits Akt signaling, cell cycle regulatory proteins, NF-κB function, as well as activity of matrix metalloproteinase (MMPs), epidermal growth factor receptor (EGFR), and Cyclooxygenase-2 (COX-2). Therefore, CAPE treatment induces cell cycle arrest and apoptosis in oral cancer cells. According to the evidence that aberrations in the EGFR/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling, NF-κB function, COX-2 activity, and MMPs activity are frequently found in oral cancers, and that the phosphorylation of Akt, EGFR, and COX-2 correlates to oral cancer patient survival and clinical progression, we believe that CAPE treatment will be useful for treatment of advanced oral cancer patients. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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Pathological Bases for a Robust Application of Cancer Molecular Classification

by Salvador J. Diaz-Cano

Int. J. Mol. Sci. 2015, 16(4), 8655-8675; https://doi.org/10.3390/ijms16048655 - 17 Apr 2015

Cited by 9 | Viewed by 7933

Abstract

Any robust classification system depends on its purpose and must refer to accepted standards, its strength relying on predictive values and a careful consideration of known factors that can affect its reliability. In this context, a molecular classification of human cancer must refer [...] Read more.

Any robust classification system depends on its purpose and must refer to accepted standards, its strength relying on predictive values and a careful consideration of known factors that can affect its reliability. In this context, a molecular classification of human cancer must refer to the current gold standard (histological classification) and try to improve it with key prognosticators for metastatic potential, staging and grading. Although organ-specific examples have been published based on proteomics, transcriptomics and genomics evaluations, the most popular approach uses gene expression analysis as a direct correlate of cellular differentiation, which represents the key feature of the histological classification. RNA is a labile molecule that varies significantly according with the preservation protocol, its transcription reflect the adaptation of the tumor cells to the microenvironment, it can be passed through mechanisms of intercellular transference of genetic information (exosomes), and it is exposed to epigenetic modifications. More robust classifications should be based on stable molecules, at the genetic level represented by DNA to improve reliability, and its analysis must deal with the concept of intratumoral heterogeneity, which is at the origin of tumor progression and is the byproduct of the selection process during the clonal expansion and progression of neoplasms. The simultaneous analysis of multiple DNA targets and next generation sequencing offer the best practical approach for an analytical genomic classification of tumors. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment)

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