Abstract
The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.
Highlights
Free from the adherens junctions, cytosolic β-catenin may have two different fates. It is degraded by the destruction complex compounded by adenomatous polyposis coli (APC), a tumor suppressor frequently mutated in colorectal cancer, or either it translocates to the cell nucleus, where it interacts with T-cell factor (TCF)/Lymphoid enhancer-binding factor (Lef) family of transcription factors
Proteins that influence FOLFOX response emerge as genes that may potentially be triggered by the epithelial-mesenchymal transition (EMT)/mesenchymal-epithelial transition (MET) dynamics during the evolution of the disease, contributing to the onset of acquired chemoresistance, which would add a new layer of complexity to the phenomena that lead to therapeutic failure in Colorectal cancer (CRC)
Regarding genes that predict the response to oxaliplatin-based chemotherapy, upregulation of SNAIL, SLUG and ZEB1/ZEB2 have been linked to overexpression of ERCC1 in colon cancer, head and neck cancer, and NSCLC cell lines, which was associated with cisplatin resistance in the latter [33,34,35]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Better screening, improved diagnostic techniques, and novel treatments have progressively increased the survival for patients diagnosed with CRC since 1970, patients diagnosed with distant-stage disease face unpromising odds with a five-year relative survival rate of only 14%, which is attributed to the development of acquired resistance to chemotherapy schemes [2,8]. For this reason, it is important to explore the molecular mechanisms involved in the development of chemoresistance in mCRC, to understand the pathways that contribute to the survival of tumor cells in patients undergoing chemotherapy, and to develop new therapeutic strategies that address these mechanisms
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