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INTERNATIONAL CONGRESS OF

CancerGenetics

• Role of Epigenetically Regulated microRNAs in Gemcitabine Resistance in Pancreatic Cancer

• Artemis Azad Aza,^1,* Elena Ebrahimian,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: Pancreatic cancer (PC) has a five-year survival rate of less than 10%, making it one of the deadliest cancers worldwide. By 2040, it is anticipated that both the incidence and death rates would have increased considerably. Therapeutic results are still subpar even with advancements in multimodal therapies such as surgery, chemotherapy, and targeted treatments. One of the most effective chemotherapeutic treatments for pancreatic cancer for a long time has been gemcitabine. Gemcitabine resistance, on the other hand, is a significant clinical problem as it reduces the medication's effectiveness and speeds up the course of the illness. Averaging 22 nucleotides in length, microRNAs (miRNAs) are tiny non-coding RNA molecules that play a critical role in post-transcriptional regulation of gene expression. More and more data points to miRNAs as major contributors to pancreatic cancer medication resistance. Crucially, epigenetic changes, including histone modifications and DNA methylation, significantly control miRNA expression and hence support chemoresistance. Our goal in doing this study is to clarify the distinct functions of different miRNAs and the impact of epigenetic control on their involvement in mediating gemcitabine resistance in pancreatic cancer.
• Methods: This review was conducted using PubMed, Web of Science, Scopus, and Google Scholar databases. It employed a combination of keywords and phrases, including MicroRNAs, Epigenetic Regulation, Gemcitabine Resistance, Pancreatic Cancer
• Results: Important modulators of the gemcitabine response in pancreatic cancer have been shown to include a number of miRNAs: • miR-21: Targeting PTEN, miR-21 activates the PI3K/Akt pathway, promoting cell survival and conferring resistance to gemcitabine. It is often overexpressed in pancreatic cancers. A bad prognosis is significantly linked to its overexpression. • miR-34a: Promoter hypermethylation frequently inhibits the production of this tumor suppressor. Deregulation of apoptotic pathways and reduced gemcitabine sensitivity result from loss of miR-34a. It has been demonstrated that miR-34a restoration improves chemosensitivity. • The miR-200 genes (miR-200c, miR-141): This family's downregulation promotes tumor invasiveness and treatment resistance by inducing the epithelial-mesenchymal transition (EMT), in part through epigenetic silencing. The NF-κB signaling pathway is activated by miR-155, which is epigenetically increased in resistant cells and contributes to gemcitabine resistance and aggressive tumor behavior. • miR-101: Targets HDAC6 to limit tumor growth. Its downregulation promotes chemoresistance in resistant pancreatic cancer cells by increasing histone deacetylation and impairing apoptosis. All of these results show that gemcitabine resistance in pancreatic cancer is influenced by both tumor-suppressive and oncogenic miRNAs that are controlled by epigenetic processes.
• Conclusion: The critical role that epigenetically controlled miRNAs play in mediating gemcitabine resistance in pancreatic cancer is highlighted by this review. Methylation typically silences tumor suppressive miRNAs, including miR-34a and miR-200c, which lowers chemosensitivity. On the other hand, pro-survival signaling pathways like PI3K/Akt and NF-κB are activated by epigenetically elevated carcinogenic miRNAs like miR-21 and miR-155. These complex regulatory networks demonstrate the promise of epigenetic treatments to restore miRNA function and overcome gemcitabine resistance, as well as the possibility of miRNA-based biomarkers for medication response prediction.
• Keywords: MicroRNAs, Epigenetic, Gemcitabine, Pancreatic Neoplasms