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.

中文翻译：

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大肠癌对FOLFOX耐药的上皮-间充质转化和microRNA。

基于5-氟尿嘧啶和奥沙利铂联合的FOLFOX方案是诊断为转移性结直肠癌患者最常使用的化疗方案。然而，化学抗性的发展是与此疾病相关的主要挑战之一。据报道，上皮-间质转化（EMT）与microRNA驱动的肿瘤细胞对5-氟尿嘧啶和奥沙利铂反应的调节有关。此外，从药物基因组学研究得知，编码二氢嘧啶脱氢酶（DPYD），胸苷酸合酶（TYMS），亚甲基四氢叶酸还原酶（MTHFR），DNA修复酶ERCC1，ERCC2和XRCC1和2期酶GSTP1削弱了对FOLFOX的反应。已经观察到EMT与DPYD，TYMS，ERCC1和GSTP1的过表达有关。在这篇综述中，我们研究了miRNA在肿瘤细胞中作为EMT启动子的作用，及其对DPYD，TYMS，MTHFR，ERCC1，ERCC2，XRCC1和GSTP1上调的潜在影响。表达，这将导致CRC肿瘤细胞对5-氟尿嘧啶和奥沙利铂的抗性。这构成了表观遗传调控的潜在机制，参与了FOLFOX化疗后的mCRC患者迟发性获得性耐药。这些生物标志物microRNA的表达可以用作个性化医学的工具，并在将来成为潜在的治疗靶标。