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INTERNATIONAL CONGRESS OF

CancerGenetics

• Epigenetically Regulated MicroRNAs in Oxaliplatin Resistance in Colorectal Cancer

• Elena Ebrahimian,^1,* Artemis Azad Ara,² Reza Assaran-Darban ,³
  1. Department of Biology, Faculty of Basic Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran
  2. Department of Biology, Faculty of Basic Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran
  3. Department of Biology Mashhad Branch, Islamic Azad University Mashhad Iran
  
  
  
• Introduction: Globally, colorectal cancer (CRC) continues to be the second most deadly kind of cancer. Incidence rates are predicted to significantly increase by 2040. Although improvements in treatment approaches, like as chemotherapy, have led to better patient outcomes, a significant clinical problem that limits treatment effectiveness and accelerates the course of the illness is the emergence of resistance to frontline drugs like oxaliplatin. The small, non-coding RNA sequences known as miRNAs are present in non-coding sections of the genome and average 22 nucleotides in length. These miRNAs are key post-transcriptional regulators and they are increasingly recognized for their role in this resistance. It is becoming well acknowledged that epigenetic changes, including DNA methylation, are important regulators of gene expression in cancer, particularly that of miRNAs, and play a significant role in chemoresistance. In this review, we aim to elucidate the specific roles of various miRNAs and the influence of epigenetic regulation on their function in driving oxaliplatin resistance in colorectal cancer.
• Methods: In this review, we conducted an extensive literature search using the PubMed, Web of Science, Scopus, and Google Scholar databases. We employed a combination of keywords and phrases, including MicroRNAs, Epigenetically Regulated, Oxaliplatin Resistance, and Colorectal Cancer.
• Results: It has been demonstrated that overexpression of miR-143 increases chemosensitivity to oxaliplatin by decreasing IGF-IR, a crucial regulator of cell survival and proliferation. This inhibition makes cancer cells more susceptible to the drug's cytotoxic effects, which makes it easier to destroy them. Notably, miR-143 is considered a tumor suppressor, and its downregulation in CRC tissues has been linked to increased expression of DNMT3A (DNA methyltransferase 3A). Furthermore, methylation of the MIR145 core promoter has been identified as a potent epigenetic regulator of the miR-143/145 cluster in CRC. On the other hand, elevated FOXQ1 transcriptional activity has been linked to oxaliplatin resistance via activating pro-survival pathways including Wnt and TGF-β1. Through encouraging drug evasion, this improved signaling prevents the death of cancer cells. Remarkably, in vitro data indicate that overexpression of miR-106a may neutralize FOXQ1-mediated resistance, resulting in heightened oxaliplatin sensitivity. It seems that miR-106a promotes the death of cancer cells by suppressing FOXQ1. MiR-106a has a role in mediating oxaliplatin sensitivity in colorectal cancer, and its overexpression can enhance this sensitivity by directly repressing FOXQ1 expression. Interestingly, a decrease in miR-106a levels has been reported to predict reduced disease-free survival and overall survival times in patients with colorectal cancer. It has been noted that overexpression of miR-454-3p in oxaliplatin-resistant cells targets PTEN to activate the PI3K/Akt pathway. Drug resistance is a result of this pro-survival pathway activation, which also hinders the elimination of cancer cells. In resistant cell lines, miR-23b knockdown studies have shown a decrease in EMT markers and a return of chemosensitivity. This implies that by preventing the development of a more resistant phenotype, blocking miR-23b can aid in the killing of cancer cells. In cells resistant to oxaliplatin, downregulation of members of the miR-200 family, including miR-200c and miR-141, is linked to activation of factors that promote EMT, such as vimentin and ZEB1. Because EMT increases motility and drug resistance, it prevents the killing of cancer cells.
• Conclusion: In conclusion, this review highlights the significant role of epigenetically regulated miRNAs in oxaliplatin resistance in colorectal cancer. Specific miRNAs like miR-143 and miR-106a, influenced by methylation, can enhance chemosensitivity. Conversely, dysregulation of other miRNAs, potentially through epigenetic mechanisms, contributes to resistance via pathways like PI3K/Akt and EMT. Understanding these intricate interactions offers promising avenues for biomarker development and targeted therapeutic strategies to overcome oxaliplatin resistance.
• Keywords: MicroRNAs, Epigenetic, Oxaliplatin, Colorectal Neoplasms