International Journal of Molecular Sciences

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20 pages, 2808 KiB

Open AccessArticle

Core Fucosylation Mediated by the FucT-8 Enzyme Affects TRAIL-Induced Apoptosis and Sensitivity to Chemotherapy in Human SW480 and SW620 Colorectal Cancer Cells

by Rubén López-Cortés, Isabel Correa Pardo, Laura Muinelo-Romay, Almudena Fernández-Briera and Emilio Gil-Martín

Int. J. Mol. Sci. 2023, 24(15), 11879; https://doi.org/10.3390/ijms241511879 - 25 Jul 2023

Cited by 5 | Viewed by 1796

Abstract

Epithelial cells can undergo apoptosis by manipulating the balance between pro-survival and apoptotic signals. In this work, we show that TRAIL-induced apoptosis can be differentially regulated by the expression of α(1,6)fucosyltransferase (FucT-8), the only enzyme in mammals that transfers the α(1,6)fucose residue to [...] Read more.

Epithelial cells can undergo apoptosis by manipulating the balance between pro-survival and apoptotic signals. In this work, we show that TRAIL-induced apoptosis can be differentially regulated by the expression of α(1,6)fucosyltransferase (FucT-8), the only enzyme in mammals that transfers the α(1,6)fucose residue to the pentasaccharide core of complex N-glycans. Specifically, in the cellular model of colorectal cancer (CRC) progression formed using the human syngeneic lines SW480 and SW620, knockdown of the FucT-8-encoding FUT8 gene significantly enhanced TRAIL-induced apoptosis in SW480 cells. However, FUT8 repression did not affect SW620 cells, which suggests that core fucosylation differentiates TRAIL-sensitive premetastatic SW480 cells from TRAIL-resistant metastatic SW620 cells. In this regard, we provide evidence that phosphorylation of ERK1/2 kinases can dynamically regulate TRAIL-dependent apoptosis and that core fucosylation can control the ERK/MAPK pro-survival pathway in which SW480 and SW620 cells participate. Moreover, the depletion of core fucosylation sensitises primary tumour SW480 cells to the combination of TRAIL and low doses of 5-FU, oxaliplatin, irinotecan, or mitomycin C. In contrast, a combination of TRAIL and oxaliplatin, irinotecan, or bevacizumab reinforces resistance of FUT8-knockdown metastatic SW620 cells to apoptosis. Consequently, FucT-8 could be a plausible target for increasing apoptosis and drug response in early CRC. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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20 pages, 2263 KiB

Open AccessArticle

Analysis of MMP-2-735C/T (rs2285053) and MMP-9-1562C/T (rs3918242) Polymorphisms in the Risk Assessment of Developing Lung Cancer

by Katarzyna Wadowska, Piotr Błasiak, Adam Rzechonek and Mariola Śliwińska-Mossoń

Int. J. Mol. Sci. 2023, 24(13), 10576; https://doi.org/10.3390/ijms241310576 - 24 Jun 2023

Cited by 6 | Viewed by 1440

Abstract

Matrix metalloproteinase (MMP)-2 and -9 are gelatinases which are capable of degrading type IV collagen and have been linked to cancer invasion and metastatic development. MMP-2 and MMP-9 gene polymorphisms may affect their biological function, and thus their role in cancer development and [...] Read more.

Matrix metalloproteinase (MMP)-2 and -9 are gelatinases which are capable of degrading type IV collagen and have been linked to cancer invasion and metastatic development. MMP-2 and MMP-9 gene polymorphisms may affect their biological function, and thus their role in cancer development and progression. We analyzed the association of the polymorphism frequencies of MMP-2-735C/T and MMP-9-1562C/T with MMP-2 and MMP-9 serum concentrations, as well as their potential effects in lung cancer patients. We conducted a retrospective, case-control study consisting of 112 lung cancer patients and 100 healthy individuals from a Caucasian population in Poland. Polymerase chain reaction with restriction fragment length polymorphism (PCR/RFLP) and electrophoresis was used to genotype genomic DNA from whole blood samples. MMP-2 and MMP-9 serum concentrations were then determined using ELISA. For statistical analysis, Statistica version 13 from TIBCO Software Inc. was utilized with a significance level <0.05. Logistic regression analysis revealed that MMP-2-735CC (OR = 5.39; 95% CI = 0.62–47.17; p = 0.238504) and -735CT genotype (OR = 7.22; 95% CI = 0.78–67.14; p = 0.072836), as well as MMP-9-1562CC (OR = 1.45; 95% CI = 0.31–6.70; p = 0.757914) and -1562CT genotype (OR = 1.60; 95% CI = 0.33–7.83; p = 0.548801) were associated with a higher risk of lung cancer. There were statistically significant differences observed in the MMP-2 concentration between individuals with the -735CC genotype and the -735CT genotype (non-smoking control: 204.04 ng/mL vs. 237.00 ng/mL, respectively, p = 0.041479; adenocarcinoma patients: 157.69 ng/mL vs. 126.37 ng/mL, respectively, p = 0.013222), as well as differences in the MMP-9 concentration between individuals with the -1562CC genotype and the -1562CT genotype (smoking control: 385.67 ng/mL vs. 562.80 ng/mL, respectively, p = 0.000936; patients with other lung neoplasms: 821.64 ng/mL vs. 928.88 ng/mL, respectively p = 0.023315). The role of MMP-2-735C/T and MMP-9 -1562C/T polymorphisms in an increased risk of lung cancer cannot be dismissed. Specific genotypes affect MMP-2 and MMP-9 concentrations in both lung cancer patients and healthy controls, which may thereby increase lung cancer risk, disease aggressiveness, and patient survival outcomes. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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17 pages, 2640 KiB

Open AccessArticle

A Novel Gemcitabine-Resistant Gallbladder Cancer Model Provides Insights into Molecular Changes Occurring during Acquired Resistance

by Luis Vergara-Gómez, Carolina Bizama, Jun Zhong, Kurt Buchegger, Felipe Suárez, Lorena Rosa, Carmen Ili, Helga Weber, Javiera Obreque, Karena Espinoza, Gabriela Repetto, Juan C. Roa, Pamela Leal and Patricia García

Int. J. Mol. Sci. 2023, 24(8), 7238; https://doi.org/10.3390/ijms24087238 - 14 Apr 2023

Cited by 2 | Viewed by 2944

Abstract

Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but the effectiveness of any regimen is limited and recurrence rates are high. Here, we investigated the molecular mechanisms of acquired resistance in GBC through the development and [...] Read more.

Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but the effectiveness of any regimen is limited and recurrence rates are high. Here, we investigated the molecular mechanisms of acquired resistance in GBC through the development and characterization of two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR). Morphological changes, cross-resistance, and migratory/invasive capabilities were evaluated. Then, microarray-based transcriptome profiling and quantitative SILAC-based phosphotyrosine proteomic analyses were performed to identify biological processes and signaling pathways dysregulated in gemcitabine-resistant GBC cells. The transcriptome profiling of parental and gemcitabine-resistant cells revealed the dysregulation of protein-coding genes that promote the enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, the phosphoproteomics analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as ABL1, PDGFRA, and LYN, which could be novel therapeutic targets in GBC. Accordingly, NOZ GemR showed increased sensitivity toward the multikinase inhibitor dasatinib compared to parental cells. Our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant GBC cells, which greatly expands our understanding of the underlying mechanisms of acquired drug resistance in GBC. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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20 pages, 8441 KiB

Open AccessArticle

Association of SNPs in the PAI1 Gene with Disease Recurrence and Clinical Outcome in Bladder Cancer

by Kaoru Murakami, Hideki Furuya, Kanani Hokutan, Steve Goodison, Ian Pagano, Runpu Chen, Cheng-Huang Shen, Michael W. Y. Chan, Chi Fai Ng, Takashi Kobayashi, Osamu Ogawa, Makito Miyake, Mark Thornquist, Yoshiko Shimizu, Kazukuni Hayashi, Zhangwei Wang, Herbert Yu and Charles J. Rosser

Int. J. Mol. Sci. 2023, 24(5), 4943; https://doi.org/10.3390/ijms24054943 - 3 Mar 2023

Cited by 4 | Viewed by 2441

Abstract

Purpose: Bladder cancer (BCa) is one of the most common cancer types worldwide and is characterized by a high rate of recurrence. In previous studies, we and others have described the functional influence of plasminogen activator inhibitor-1 (PAI1) in bladder cancer development. While [...] Read more.

Purpose: Bladder cancer (BCa) is one of the most common cancer types worldwide and is characterized by a high rate of recurrence. In previous studies, we and others have described the functional influence of plasminogen activator inhibitor-1 (PAI1) in bladder cancer development. While polymorphisms in PAI1 have been associated with increased risk and worsened prognosis in some cancers, the mutational status of PAI1 in human bladder tumors has not been well defined. Methods: In this study, we evaluated the mutational status of PAI1 in a series of independent cohorts, comprised of a total of 660 subjects. Results: Sequencing analyses identified two clinically relevant 3′ untranslated region (UTR) single nucleotide polymorphisms (SNPs) in PAI1 (rs7242; rs1050813). Somatic SNP rs7242 was present in human BCa cohorts (overall incidence of 72%; 62% in Caucasians and 72% in Asians). In contrast, the overall incidence of germline SNP rs1050813 was 18% (39% in Caucasians and 6% in Asians). Furthermore, Caucasian patients with at least one of the described SNPs had worse recurrence-free survival and overall survival (p = 0.03 and p = 0.03, respectively). In vitro functional studies demonstrated that SNP rs7242 increased the anti-apoptotic effect of PAI1, and SNP rs1050813 was related to a loss of contact inhibition associated with cellular proliferation when compared to wild type. Conclusion: Further investigation of the prevalence and potential downstream influence of these SNPs in bladder cancer is warranted. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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19 pages, 5615 KiB

Open AccessArticle

Potential Early Markers for Breast Cancer: A Proteomic Approach Comparing Saliva and Serum Samples in a Pilot Study

by Indu Sinha, Rachel L. Fogle, Gizem Gulfidan, Anne E. Stanley, Vonn Walter, Christopher S. Hollenbeak, Kazim Y. Arga and Raghu Sinha

Int. J. Mol. Sci. 2023, 24(4), 4164; https://doi.org/10.3390/ijms24044164 - 19 Feb 2023

Cited by 9 | Viewed by 2838

Abstract

Breast cancer is the second leading cause of death for women in the United States, and early detection could offer patients the opportunity to receive early intervention. The current methods of diagnosis rely on mammograms and have relatively high rates of false positivity, [...] Read more.

Breast cancer is the second leading cause of death for women in the United States, and early detection could offer patients the opportunity to receive early intervention. The current methods of diagnosis rely on mammograms and have relatively high rates of false positivity, causing anxiety in patients. We sought to identify protein markers in saliva and serum for early detection of breast cancer. A rigorous analysis was performed for individual saliva and serum samples from women without breast disease, and women diagnosed with benign or malignant breast disease, using isobaric tags for relative and absolute quantitation (iTRAQ) technique, and employing a random effects model. A total of 591 and 371 proteins were identified in saliva and serum samples from the same individuals, respectively. The differentially expressed proteins were mainly involved in exocytosis, secretion, immune response, neutrophil-mediated immunity and cytokine-mediated signaling pathway. Using a network biology approach, significantly expressed proteins in both biological fluids were evaluated for protein–protein interaction networks and further analyzed for these being potential biomarkers in breast cancer diagnosis and prognosis. Our systems approach illustrates a feasible platform for investigating the responsive proteomic profile in benign and malignant breast disease using saliva and serum from the same women. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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14 pages, 1754 KiB

Open AccessArticle

Genomic and Glycolytic Entropy Are Reliable Radiogenomic Heterogeneity Biomarkers for Non-Small Cell Lung Cancer

by Yu-Hung Chen, Kun-Han Lue, Chih-Bin Lin, Kuang-Chi Chen, Sheng-Chieh Chan, Sung-Chao Chu, Bee-Song Chang and Yen-Chang Chen

Int. J. Mol. Sci. 2023, 24(4), 3988; https://doi.org/10.3390/ijms24043988 - 16 Feb 2023

Cited by 3 | Viewed by 1848

Abstract

Radiogenomic heterogeneity features in ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) have become popular in non-small cell lung cancer (NSCLC) research. However, the reliabilities of genomic heterogeneity features and of PET-based glycolytic features in different image matrix sizes have yet to [...] Read more.

Radiogenomic heterogeneity features in ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) have become popular in non-small cell lung cancer (NSCLC) research. However, the reliabilities of genomic heterogeneity features and of PET-based glycolytic features in different image matrix sizes have yet to be thoroughly tested. We conducted a prospective study with 46 NSCLC patients to assess the intra-class correlation coefficient (ICC) of different genomic heterogeneity features. We also tested the ICC of PET-based heterogeneity features from different image matrix sizes. The association of radiogenomic features with clinical data was also examined. The entropy-based genomic heterogeneity feature (ICC = 0.736) is more reliable than the median-based feature (ICC = −0.416). The PET-based glycolytic entropy was insensitive to image matrix size change (ICC = 0.958) and remained reliable in tumors with a metabolic volume of <10 mL (ICC = 0.894). The glycolytic entropy is also significantly associated with advanced cancer stages (p = 0.011). We conclude that the entropy-based radiogenomic features are reliable and may serve as ideal biomarkers for research and further clinical use for NSCLC. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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12 pages, 7860 KiB

Open AccessArticle

The Prognostic Value of Cancer Stem Cell Markers (CSCs) Expression—ALDH1A1, CD133, CD44—For Survival and Long-Term Follow-Up of Ovarian Cancer Patients

by Natalia Izycka, Marcin Rucinski, Malgorzata Andrzejewska, Sebastian Szubert, Ewa Nowak-Markwitz and Karolina Sterzynska

Int. J. Mol. Sci. 2023, 24(3), 2400; https://doi.org/10.3390/ijms24032400 - 25 Jan 2023

Cited by 6 | Viewed by 2479

Abstract

Recurrent disease and treatment-associated chemoresistance are the two main factors accounting for poor clinical outcomes of ovarian cancer (OC) patients. Both can be associated with cancer stem cells (CSCs), which contribute to cancer formation, progression, chemoresistance, and recurrence. Hence, this study investigated whether [...] Read more.

Recurrent disease and treatment-associated chemoresistance are the two main factors accounting for poor clinical outcomes of ovarian cancer (OC) patients. Both can be associated with cancer stem cells (CSCs), which contribute to cancer formation, progression, chemoresistance, and recurrence. Hence, this study investigated whether the expression of known CSC-associated markers ALDH1A, CD44, and CD133 may predict OC patient prognosis. We analyzed their expression in primary epithelial ovarian cancer (EOC) patients using immunohistochemistry and related them to clinicopathological data, including overall survival (OS) and progression-free survival (PFS). Expression of ALDH1A1 was detected in 32%, CD133 in 28%, and CD44 in 33% of cases. While Kaplan–Meier analysis revealed no association of the expression of CD133 and CD44 with PFS and OS, ALDH1A1-positive patients were characterized with both significantly shorter OS (p = 0.00022) and PFS (p = 0.027). Multivariate analysis demonstrated that the expression of ALDH1A1, FIGO stage III–IV, and residual disease after suboptimal debulking or neoadjuvant chemotherapy correlated with shorter OS. The results of this study identify ALDH1A1 as a potential independent prognostic factor of shorter OS and PFS in EOC patients. Therefore, targeting ALDH1A1-positive cancer cells may be a promising therapeutic strategy to influence the disease course and treatment response. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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18 pages, 4334 KiB

Open AccessArticle

by Yipeng Pang, Yushi Wang, Xinyu Zhou, Zhu Ni, Wenjing Chen, Yi Liu and Wenlong Du

Int. J. Mol. Sci. 2023, 24(2), 1464; https://doi.org/10.3390/ijms24021464 - 11 Jan 2023

Cited by 10 | Viewed by 3134

Abstract

Cuproptosis, a new cell death pattern, is promising as an intervention target to treat tumors. Abnormal long non-coding RNA (lncRNA) expression is closely associated with the occurrence and development of papillary renal cell carcinoma (pRCC). However, cuproptosis-related lncRNAs (CRLs) remain largely unknown as [...] Read more.

Cuproptosis, a new cell death pattern, is promising as an intervention target to treat tumors. Abnormal long non-coding RNA (lncRNA) expression is closely associated with the occurrence and development of papillary renal cell carcinoma (pRCC). However, cuproptosis-related lncRNAs (CRLs) remain largely unknown as prognostic markers for pRCC. We aimed to forecast the prognosis of pRCC patients by constructing models according to CRLs and to examine the correlation between the signatures and the inflammatory microenvironment. From the Cancer Genome Atlas (TCGA), RNA sequencing, genomic mutations and clinical data of TCGA-KIRP (Kidney renal papillary cell carcinoma) were analyzed. Randomly selected pRCC patients were allotted to the training and testing sets. To determine the independent prognostic impact of the training characteristic, the least absolute shrinkage and selection operator (LASSO) algorithm was utilized, together with univariate and multivariate Cox regression models. Further validation was performed in the testing and whole cohorts. External datasets were utilized to verify the prognostic value of CRLs as well. The CRLs prognostic features in pRCC were established based on the five CRLs (AC244033.2, LINC00886, AP000866.1, MRPS9-AS1 and CKMT2-AS1). The utility of CRLs was evaluated and validated in training, testing and all sets on the basis of the Kaplan–Meier (KM) survival analysis. The risk score could be a robust prognostic factor to forecast clinical outcomes for pRCC patients by the LASSO algorithm and univariate and multivariate Cox regression. Analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) data demonstrated that differentially expressed genes (DEGs) are primarily important for immune responses and the PI3K-Akt pathway. Arachidonic acid metabolism was enriched in the high-risk set by Gene Set Enrichment Analysis (GSEA). In addition, Tumor Immune Dysfunction and Exclusion (TIDE) analysis suggested that there was a high risk of immune escape in the high-risk cohort. The immune functions of the low- and high-risk sets differed significantly based on immune microenvironment analysis. Finally, four drugs were screened with a higher sensitivity to the high-risk set. Taken together, a novel model according to five CRLs was set up to forecast the prognosis of pRCC patients, which provides a potential strategy to treat pRCC by a combination of cuproptosis and immunotherapy. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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19 pages, 5409 KiB

Open AccessArticle

Reclassification of TCGA Diffuse Glioma Profiles Linked to Transcriptomic, Epigenetic, Genomic and Clinical Data, According to the 2021 WHO CNS Tumor Classification

by Galina Zakharova, Victor Efimov, Mikhail Raevskiy, Pavel Rumiantsev, Alexander Gudkov, Oksana Belogurova-Ovchinnikova, Maksim Sorokin and Anton Buzdin

Int. J. Mol. Sci. 2023, 24(1), 157; https://doi.org/10.3390/ijms24010157 - 21 Dec 2022

Cited by 13 | Viewed by 3940

Abstract

In 2021, the fifth edition of the WHO classification of tumors of the central nervous system (WHO CNS5) was published. Molecular features of tumors were directly incorporated into the diagnostic decision tree, thus affecting both the typing and staging of the tumor. It [...] Read more.

In 2021, the fifth edition of the WHO classification of tumors of the central nervous system (WHO CNS5) was published. Molecular features of tumors were directly incorporated into the diagnostic decision tree, thus affecting both the typing and staging of the tumor. It has changed the traditional approach, based solely on histopathological classification. The Cancer Genome Atlas project (TCGA) is one of the main sources of molecular information about gliomas, including clinically annotated transcriptomic and genomic profiles. Although TCGA itself has played a pivotal role in developing the WHO CNS5 classification, its proprietary databases still retain outdated diagnoses which frequently appear incorrect and misleading according to the WHO CNS5 standards. We aimed to define the up-to-date annotations for gliomas from TCGA’s database that other scientists can use in their research. Based on WHO CNS5 guidelines, we developed an algorithm for the reclassification of TCGA glioma samples by molecular features. We updated tumor type and diagnosis for 828 out of a total of 1122 TCGA glioma cases, after which available transcriptomic and methylation data showed clustering features more consistent with the updated grouping. We also observed better stratification by overall survival for the updated diagnoses, yet WHO grade 3 IDH-mutant oligodendrogliomas and astrocytomas are still indistinguishable. We also detected altered performance in the previous diagnostic transcriptomic molecular biomarkers (expression of SPRY1, CRNDE and FREM2 genes and FREM2 molecular pathway) and prognostic gene signature (FN1, ITGA5, OSMR, and NGFR) after reclassification. Thus, we conclude that further efforts are needed to reconsider glioma molecular biomarkers. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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14 pages, 4998 KiB

Open AccessArticle

Glioblastoma Molecular Classification Tool Based on mRNA Analysis: From Wet-Lab to Subtype

by Giedrius Steponaitis, Vytautas Kucinskas, Ieva Golubickaite, Kestutis Skauminas and Ausra Saudargiene

Int. J. Mol. Sci. 2022, 23(24), 15875; https://doi.org/10.3390/ijms232415875 - 14 Dec 2022

Cited by 3 | Viewed by 1855

Abstract

Most glioblastoma studies incorporate the layer of tumor molecular subtype based on the four-subtype classification system proposed in 2010. Nevertheless, there is no universally recognized and convenient tool for glioblastoma molecular subtyping, and each study applies a different set of markers and/or approaches [...] Read more.

Most glioblastoma studies incorporate the layer of tumor molecular subtype based on the four-subtype classification system proposed in 2010. Nevertheless, there is no universally recognized and convenient tool for glioblastoma molecular subtyping, and each study applies a different set of markers and/or approaches that cause inconsistencies in data comparability and reproducibility between studies. Thus, this study aimed to create an applicable user-friendly tool for glioblastoma classification, with high accuracy, while using a significantly smaller number of variables. The study incorporated a TCGA microarray, sequencing datasets, and an independent cohort of 56 glioblastomas (LUHS cohort). The models were constructed by applying the Agilent G4502 dataset, and they were tested using the Affymetrix HG-U133a and Illumina Hiseq cohorts, as well as the LUHS cases. Two classification models were constructed by applying a logistic regression classification algorithm, based on the mRNA levels of twenty selected genes. The classifiers were translated to a RT-qPCR assay and validated in an independent cohort of 56 glioblastomas. The classification accuracy of the 20-gene and 5-gene classifiers varied between 90.7–91% and 85.9–87.7%, respectively. With this work, we propose a cost-efficient three-class (classical, mesenchymal, and proneural) tool for glioblastoma molecular classification based on the mRNA analysis of only 5–20 genes, and we provide the basic information for classification performance starting from the wet-lab stage. We hope that the proposed classification tool will enable data comparability between different research groups. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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12 pages, 1810 KiB

Open AccessArticle

MicroRNA-19b Plays a Key Role in 5-Fluorouracil Resistance and Predicts Tumor Progression in Locally Advanced Rectal Cancer Patients

by Andrea Santos, Ion Cristóbal, Jaime Rubio, Cristina Caramés, Melani Luque, Marta Sanz-Álvarez, Sandra Zazo, Juan Madoz-Gúrpide, Federico Rojo and Jesus García-Foncillas

Int. J. Mol. Sci. 2022, 23(20), 12447; https://doi.org/10.3390/ijms232012447 - 18 Oct 2022

Cited by 3 | Viewed by 1740

Abstract

The standard clinical management of locally advanced rectal cancer (LARC) patients includes neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) followed by mesorectal excision. MicroRNA (miR)-19b expression levels in LARC biopsies obtained from initial colonoscopy have recently been identified as independent predictors of both patient outcome [...] Read more.

The standard clinical management of locally advanced rectal cancer (LARC) patients includes neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) followed by mesorectal excision. MicroRNA (miR)-19b expression levels in LARC biopsies obtained from initial colonoscopy have recently been identified as independent predictors of both patient outcome and pathological response to preoperative CRT in this disease. Moreover, it has been discovered that this miR increases its expression in 5-FU resistant colon cancer cells after 5-FU exposure. Despite the fact that these observations suggest a functional role of miR-19b modulating 5-FU response of LARC cells, this issue still remains to be clarified. Here, we show that downregulation of miR-19b enhances the antitumor effects of 5-FU treatment. Moreover, ectopic miR-19b modulation was able to restore sensitivity to 5-FU treatment using an acquired resistant model to this compound. Notably, we also evaluated the potential clinical impact of miR-19b as a predictive marker of disease progression after tumor surgery resection in LARC patients, observing that miR-19b overexpression significantly anticipates patient recurrence in our cohort (p = 0.002). Altogether, our findings demonstrate the functional role of miR-19b in the progressively decreasing sensitivity to 5-FU treatment and its potential usefulness as a therapeutic target to overcome 5-FU resistance, as well as its clinical impact as predictor of tumor progression and relapse. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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13 pages, 4802 KiB

Open AccessArticle

Aurora Kinase A and Bcl-xL Inhibition Suppresses Metastasis in Triple-Negative Breast Cancer

by Natascha Skov, Carla L. Alves, Sidse Ehmsen and Henrik J. Ditzel

Int. J. Mol. Sci. 2022, 23(17), 10053; https://doi.org/10.3390/ijms231710053 - 2 Sep 2022

Cited by 4 | Viewed by 3631

Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous disease that accounts for 10–15% of all breast cancer cases. Within TNBC, the treatment of basal B is the most challenging due to its highly invasive potential, and thus treatments to suppress metastasis formation in this [...] Read more.

Triple-negative breast cancer (TNBC) is a heterogeneous disease that accounts for 10–15% of all breast cancer cases. Within TNBC, the treatment of basal B is the most challenging due to its highly invasive potential, and thus treatments to suppress metastasis formation in this subgroup are urgently needed. However, the mechanisms underlying the metastatic ability of TNBC remain unclear. In the present study, we investigated the role of Aurora A and Bcl-xL in regulating basal B cell invasion. We found gene amplification and elevated protein expression in the basal B cells, which also showed increased invasiveness in vitro, compared to basal A cells. Chemical inhibition of Aurora A with alisertib and siRNA-mediated knockdown of BCL2L1 decreased the number of invading cells compared to non-treated cells in basal B cell lines. The analysis of the correlation between AURKA and BCL2L1 expression in TNBC and patient survival revealed significantly decreased relapse-free survival (n = 534, p = 0.012) and distant metastasis-free survival (n = 424, p = 0.017) in patients with primary tumors exhibiting a high combined expression of AURKA and BCL2L1. Together, our findings suggest that high levels of Aurora A and Bcl-xL promote metastasis, and inhibition of these proteins may suppress metastasis and improve patient survival in basal B TNBC. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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13 pages, 3276 KiB

Open AccessArticle

Blood Test for Breast Cancer Screening through the Detection of Tumor-Associated Circulating Transcripts

by Sunyoung Park, Sungwoo Ahn, Jee Ye Kim, Jungho Kim, Hyun Ju Han, Dasom Hwang, Jungmin Park, Hyung Seok Park, Seho Park, Gun Min Kim, Joohyuk Sohn, Joon Jeong, Yong Uk Song, Hyeyoung Lee and Seung Il Kim

Int. J. Mol. Sci. 2022, 23(16), 9140; https://doi.org/10.3390/ijms23169140 - 15 Aug 2022

Cited by 4 | Viewed by 3053

Abstract

Liquid biopsy has been emerging for early screening and treatment monitoring at each cancer stage. However, the current blood-based diagnostic tools in breast cancer have not been sufficient to understand patient-derived molecular features of aggressive tumors individually. Herein, we aimed to develop a [...] Read more.

Liquid biopsy has been emerging for early screening and treatment monitoring at each cancer stage. However, the current blood-based diagnostic tools in breast cancer have not been sufficient to understand patient-derived molecular features of aggressive tumors individually. Herein, we aimed to develop a blood test for the early detection of breast cancer with cost-effective and high-throughput considerations in order to combat the challenges associated with precision oncology using mRNA-based tests. We prospectively evaluated 719 blood samples from 404 breast cancer patients and 315 healthy controls, and identified 10 mRNA transcripts whose expression is increased in the blood of breast cancer patients relative to healthy controls. Modeling of the tumor-associated circulating transcripts (TACTs) is performed by means of four different machine learning techniques (artificial neural network (ANN), decision tree (DT), logistic regression (LR), and support vector machine (SVM)). The ANN model had superior sensitivity (90.2%), specificity (80.0%), and accuracy (85.7%) compared with the other three models. Relative to the value of 90.2% achieved using the TACT assay on our test set, the sensitivity values of other conventional assays (mammogram, CEA, and CA 15-3) were comparable or much lower, at 89%, 7%, and 5%, respectively. The sensitivity, specificity, and accuracy of TACTs were appreciably consistent across the different breast cancer stages, suggesting the potential of the TACTs assay as an early diagnosis and prediction of poor outcomes. Our study potentially paves the way for a simple and accurate diagnostic and prognostic tool for liquid biopsy. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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Review

Jump to: Research

42 pages, 3469 KiB

Open AccessReview

Machine Learning Models for the Identification of Prognostic and Predictive Cancer Biomarkers: A Systematic Review

by Qasem Al-Tashi, Maliazurina B. Saad, Amgad Muneer, Rizwan Qureshi, Seyedali Mirjalili, Ajay Sheshadri, Xiuning Le, Natalie I. Vokes, Jianjun Zhang and Jia Wu

Int. J. Mol. Sci. 2023, 24(9), 7781; https://doi.org/10.3390/ijms24097781 - 24 Apr 2023

Cited by 35 | Viewed by 7757

Abstract

The identification of biomarkers plays a crucial role in personalized medicine, both in the clinical and research settings. However, the contrast between predictive and prognostic biomarkers can be challenging due to the overlap between the two. A prognostic biomarker predicts the future outcome [...] Read more.

The identification of biomarkers plays a crucial role in personalized medicine, both in the clinical and research settings. However, the contrast between predictive and prognostic biomarkers can be challenging due to the overlap between the two. A prognostic biomarker predicts the future outcome of cancer, regardless of treatment, and a predictive biomarker predicts the effectiveness of a therapeutic intervention. Misclassifying a prognostic biomarker as predictive (or vice versa) can have serious financial and personal consequences for patients. To address this issue, various statistical and machine learning approaches have been developed. The aim of this study is to present an in-depth analysis of recent advancements, trends, challenges, and future prospects in biomarker identification. A systematic search was conducted using PubMed to identify relevant studies published between 2017 and 2023. The selected studies were analyzed to better understand the concept of biomarker identification, evaluate machine learning methods, assess the level of research activity, and highlight the application of these methods in cancer research and treatment. Furthermore, existing obstacles and concerns are discussed to identify prospective research areas. We believe that this review will serve as a valuable resource for researchers, providing insights into the methods and approaches used in biomarker discovery and identifying future research opportunities. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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18 pages, 1651 KiB

Open AccessReview

Long Non-Coding RNAs (lncRNAs) as Regulators of the PI3K/AKT/mTOR Pathway in Gastric Carcinoma

by Ismael Riquelme, Pablo Pérez-Moreno, Bárbara Mora-Lagos, Carmen Ili, Priscilla Brebi and Juan Carlos Roa

Int. J. Mol. Sci. 2023, 24(7), 6294; https://doi.org/10.3390/ijms24076294 - 27 Mar 2023

Cited by 17 | Viewed by 2725

Abstract

Gastric cancer (GC) represents ~10% of the global cancer-related deaths, increasingly affecting the younger population in active stages of life. The high mortality of GC is due to late diagnosis, the presence of metastasis and drug resistance development. Additionally, current clinical markers do [...] Read more.

Gastric cancer (GC) represents ~10% of the global cancer-related deaths, increasingly affecting the younger population in active stages of life. The high mortality of GC is due to late diagnosis, the presence of metastasis and drug resistance development. Additionally, current clinical markers do not guide the patient management adequately, thereby new and more reliable biomarkers and therapeutic targets are still needed for this disease. RNA-seq technology has allowed the discovery of new types of RNA transcripts including long non-coding RNAs (lncRNAs), which are able to regulate the gene/protein expression of many signaling pathways (e.g., the PI3K/AKT/mTOR pathway) in cancer cells by diverse molecular mechanisms. In addition, these lncRNAs might also be proposed as promising diagnostic or prognostic biomarkers or as potential therapeutic targets in GC. This review describes important topics about some lncRNAs that have been described as regulators of the PI3K/AKT/mTOR signaling pathway, and hence, their potential oncogenic role in the development of this malignancy. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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29 pages, 1727 KiB

Open AccessReview

Emerging RNA-Based Therapeutic and Diagnostic Options: Recent Advances and Future Challenges in Genitourinary Cancers

by Fabiana Tortora, Evelina La Civita, Pankaj Trivedi, Ferdinando Febbraio, Daniela Terracciano and Amelia Cimmino

Int. J. Mol. Sci. 2023, 24(5), 4601; https://doi.org/10.3390/ijms24054601 - 27 Feb 2023

Cited by 1 | Viewed by 2763

Abstract

Renal cell carcinoma, bladder cancer, and prostate cancer are the most widespread genitourinary tumors. Their treatment and diagnosis have significantly evolved over recent years, due to an increasing understanding of oncogenic factors and the molecular mechanisms involved. Using sophisticated genome sequencing technologies, the [...] Read more.

Renal cell carcinoma, bladder cancer, and prostate cancer are the most widespread genitourinary tumors. Their treatment and diagnosis have significantly evolved over recent years, due to an increasing understanding of oncogenic factors and the molecular mechanisms involved. Using sophisticated genome sequencing technologies, the non-coding RNAs, such as microRNAs, long non-coding RNAs, and circular RNAs, have all been implicated in the occurrence and progression of genitourinary cancers. Interestingly, DNA, protein, and RNA interactions with lncRNAs and other biological macromolecules drive some of these cancer phenotypes. Studies on the molecular mechanisms of lncRNAs have identified new functional markers that could be potentially useful as biomarkers for effective diagnosis and/or as targets for therapeutic intervention. This review focuses on the mechanisms underlying abnormal lncRNA expression in genitourinary tumors and discusses their role in diagnostics, prognosis, and treatment. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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18 pages, 533 KiB

Open AccessReview

Biomarkers of Aggressive Prostate Cancer at Diagnosis

by Brock E. Boehm, Monica E. York, Gyorgy Petrovics, Indu Kohaar and Gregory T. Chesnut

Int. J. Mol. Sci. 2023, 24(3), 2185; https://doi.org/10.3390/ijms24032185 - 22 Jan 2023

Cited by 25 | Viewed by 7812

Abstract

In the United States, prostate cancer (CaP) remains the second leading cause of cancer deaths in men. CaP is predominantly indolent at diagnosis, with a small fraction (25–30%) representing an aggressive subtype (Gleason score 7–10) that is prone to metastatic progression. This fact, [...] Read more.

In the United States, prostate cancer (CaP) remains the second leading cause of cancer deaths in men. CaP is predominantly indolent at diagnosis, with a small fraction (25–30%) representing an aggressive subtype (Gleason score 7–10) that is prone to metastatic progression. This fact, coupled with the criticism surrounding the role of prostate specific antigen in prostate cancer screening, demonstrates the current need for a biomarker(s) that can identify clinically significant CaP and avoid unnecessary biopsy procedures and psychological implications of being diagnosed with low-risk prostate cancer. Although several diagnostic biomarkers are available to clinicians, very few comparative trials have been performed to assess the clinical effectiveness of these biomarkers. It is of note, however, that a majority of these clinical trials have been over-represented by men of Caucasian origin, despite the fact that African American men have a 1.7 times higher incidence and 2.1 times higher rate of mortality from prostate cancer. Biomarkers for CaP diagnosis based on the tissue of origin include urine-based gene expression assays (PCA3, Select MDx, ExoDx Prostate IntelliScore, Mi-Prostate Score, PCA3-PCGEM1 gene panel), blood-based protein biomarkers (4K, PHI), and tissue-based DNA biomarker (Confirm MDx). Another potential direction that has emerged to aid in the CaP diagnosis include multi-parametric magnetic resonance imaging (mpMRI) and bi-parametric magnetic resonance imaging (bpMRI), which in conjunction with clinically validated biomarkers may provide a better approach to predict clinically significant CaP at diagnosis. In this review, we discuss some of the adjunctive biomarker tests along with newer imaging modalities that are currently available to help clinicians decide which patients are at risk of having high-grade CaP on prostate biopsy with the emphasis on clinical utility of the tests across African American (AA) and Caucasian (CA) men. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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20 pages, 1317 KiB

Open AccessReview

Predicting Prognosis and Platinum Resistance in Ovarian Cancer: Role of Immunohistochemistry Biomarkers

by Ghofraan Abdulsalam Atallah, Nirmala Chandralega Kampan, Kah Teik Chew, Norfilza Mohd Mokhtar, Reena Rahayu Md Zin, Mohamad Nasir bin Shafiee and Nor Haslinda binti Abd. Aziz

Int. J. Mol. Sci. 2023, 24(3), 1973; https://doi.org/10.3390/ijms24031973 - 19 Jan 2023

Cited by 20 | Viewed by 5066

Abstract

Ovarian cancer is a lethal reproductive tumour affecting women worldwide. The advancement in presentation and occurrence of chemoresistance are the key factors for poor survival among ovarian cancer women. Surgical debulking was the mainstay of systemic treatment for ovarian cancer, which was followed [...] Read more.

Ovarian cancer is a lethal reproductive tumour affecting women worldwide. The advancement in presentation and occurrence of chemoresistance are the key factors for poor survival among ovarian cancer women. Surgical debulking was the mainstay of systemic treatment for ovarian cancer, which was followed by a successful start to platinum-based chemotherapy. However, most women develop platinum resistance and relapse within six months of receiving first-line treatment. Thus, there is a great need to identify biomarkers to predict platinum resistance before enrolment into chemotherapy, which would facilitate individualized targeted therapy for these subgroups of patients to ensure better survival and an improved quality of life and overall outcome. Harnessing the immune response through immunotherapy approaches has changed the treatment way for patients with cancer. The immune outline has emerged as a beneficial tool for recognizing predictive and prognostic biomarkers clinically. Studying the tumour microenvironment (TME) of ovarian cancer tissue may provide awareness of actionable targets for enhancing chemotherapy outcomes and quality of life. This review analyses the relevance of immunohistochemistry biomarkers as prognostic biomarkers in predicting chemotherapy resistance and improving the quality of life in ovarian cancer. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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36 pages, 5197 KiB

Open AccessReview

RAGE Inhibitors for Targeted Therapy of Cancer: A Comprehensive Review

by Tabrez Faruqui, Mohd Sajid Khan, Yusuf Akhter, Salman Khan, Zeeshan Rafi, Mohd Saeed, Ihn Han, Eun-Ha Choi and Dharmendra Kumar Yadav

Int. J. Mol. Sci. 2023, 24(1), 266; https://doi.org/10.3390/ijms24010266 - 23 Dec 2022

Cited by 10 | Viewed by 3798

Abstract

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin family that is overexpressed in several cancers. RAGE is highly expressed in the lung, and its expression increases proportionally at the site of inflammation. This receptor can bind a [...] Read more.

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin family that is overexpressed in several cancers. RAGE is highly expressed in the lung, and its expression increases proportionally at the site of inflammation. This receptor can bind a variety of ligands, including advanced glycation end products, high mobility group box 1, S100 proteins, adhesion molecules, complement components, advanced lipoxidation end products, lipopolysaccharides, and other molecules that mediate cellular responses related to acute and chronic inflammation. RAGE serves as an important node for the initiation and stimulation of cell stress and growth signaling mechanisms that promote carcinogenesis, tumor propagation, and metastatic potential. In this review, we discuss different aspects of RAGE and its prominent ligands implicated in cancer pathogenesis and describe current findings that provide insights into the significant role played by RAGE in cancer. Cancer development can be hindered by inhibiting the interaction of RAGE with its ligands, and this could provide an effective strategy for cancer treatment. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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28 pages, 2381 KiB

Open AccessReview

Renal Cell Carcinoma as a Metabolic Disease: An Update on Main Pathways, Potential Biomarkers, and Therapeutic Targets

by Nicola Antonio di Meo, Francesco Lasorsa, Monica Rutigliano, Davide Loizzo, Matteo Ferro, Alessandro Stella, Cinzia Bizzoca, Leonardo Vincenti, Savio Domenico Pandolfo, Riccardo Autorino, Felice Crocetto, Emanuele Montanari, Marco Spilotros, Michele Battaglia, Pasquale Ditonno and Giuseppe Lucarelli

Int. J. Mol. Sci. 2022, 23(22), 14360; https://doi.org/10.3390/ijms232214360 - 18 Nov 2022

Cited by 84 | Viewed by 4886

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most frequent histological kidney cancer subtype. Over the last decade, significant progress has been made in identifying the genetic and metabolic alterations driving ccRCC development. In particular, an integrated approach using transcriptomics, metabolomics, and lipidomics [...] Read more.

Clear cell renal cell carcinoma (ccRCC) is the most frequent histological kidney cancer subtype. Over the last decade, significant progress has been made in identifying the genetic and metabolic alterations driving ccRCC development. In particular, an integrated approach using transcriptomics, metabolomics, and lipidomics has led to a better understanding of ccRCC as a metabolic disease. The metabolic profiling of this cancer could help define and predict its behavior in terms of aggressiveness, prognosis, and therapeutic responsiveness, and would be an innovative strategy for choosing the optimal therapy for a specific patient. This review article describes the current state-of-the-art in research on ccRCC metabolic pathways and potential therapeutic applications. In addition, the clinical implication of pharmacometabolomic intervention is analyzed, which represents a new field for novel stage-related and patient-tailored strategies according to the specific susceptibility to new classes of drugs. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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11 pages, 769 KiB

Open AccessReview

Prognostic Value of Albumin to Globulin Ratio in Non-Metastatic and Metastatic Prostate Cancer Patients: A Meta-Analysis and Systematic Review

by Stefano Salciccia, Marco Frisenda, Giulio Bevilacqua, Pietro Viscuso, Paolo Casale, Ettore De Berardinis, Giovanni Battista Di Pierro, Susanna Cattarino, Gloria Giorgino, Davide Rosati, Francesco Del Giudice, Alessandro Sciarra, Gianna Mariotti and Alessandro Gentilucci

Int. J. Mol. Sci. 2022, 23(19), 11501; https://doi.org/10.3390/ijms231911501 - 29 Sep 2022

Cited by 10 | Viewed by 1954

Abstract

The aim of our meta-analysis is to analyze data available in the literature regarding a possible prognostic value of the albumin to globulin ratio (AGR) in prostate cancer (PC) patients. We distinguished our analysis in terms of PC staging, histologic aggressiveness, and risk [...] Read more.

The aim of our meta-analysis is to analyze data available in the literature regarding a possible prognostic value of the albumin to globulin ratio (AGR) in prostate cancer (PC) patients. We distinguished our analysis in terms of PC staging, histologic aggressiveness, and risk of progression after treatments. A literature search process was performed (“prostatic cancer”, “albumin”, “globulin”, “albumin to globulin ratio”) following the PRISMA guidelines. In our meta-analysis, the pooled Event Rate (ER) estimate for each group of interest was calculated using a random effect model. Cases were distinguished in Low and High AGR groups based on an optimal cut-off value defined at ROC analysis. Four clinical trials were enclosed (sample size range from 214 to 6041 cases). The pooled Risk Difference for a non-organ confined PC between High AGR and Low AGR cases was −0.05 (95%CI: −0.12–0.01) with a very low rate of heterogeneity (I² < 0.15%; p = 0.43) among studies (test of group differences p = 0.21). In non-metastatic PC cases, the pooled Risk Difference for biochemical progression (BCP) between High AGR and Low AGR cases was −0.05 (95%CI: −0.12–0.01) (I² = 0.01%; p = 0.69) (test of group differences p = 0.12). In metastatic PC cases, AGR showed an independent significant (p < 0.01) predictive value either in terms of progression free survival (PFS) (Odds Ratio (OR): 0.642 (0.430–0.957)) or cancer specific survival (CSS) (OR: 0.412 (0.259–0.654)). Our meta-analysis showed homogeneous results supporting no significant predictive values for AGR in terms of staging, grading and biochemical progression in non-metastatic PC. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Cancer and Their Applications)

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