مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
Epigenetic Reprogramming with RNA Molecules: A New Frontier in Combating Drug-Resistant Gastric Cancer
Epigenetic Reprogramming with RNA Molecules: A New Frontier in Combating Drug-Resistant Gastric Cancer
Neda Abdi,1,*Nooshafarin Shirani,2
1. Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran. 2. Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
Introduction: Gastric cancer (GC) is the fourth most common cause of death globally, and drug resistance remains a significant hurdle to its treatment efficiency. New findings discuss that epigenetic dysregulation, especially DNA methylation, histone modification, and non-coding RNA activity, is of great importance in conferring chemoresistance. A variety of RNA molecules, including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and small interfering RNAs (siRNAs), are now being considered as a tool to reprogram tumor cells resistant to drugs.
Methods: For a thorough literature review, databases such as PubMed, Web of Science, and Embase were used. The timeline was set from 2015 to 2024 and the keywords included "gastric cancer", "chemoresistance", "epigenetics", "DNA methylation", "lncRNA", "circRNA", "RNA therapeutics", "siRNA", and "miRNA". After application of a number of filters (e.g., peer-reviewed studies, preclinical/clinical trials, etc.), the studies were carefully selected and the information were summarized accordingly. Both in vivo and in vitro studies were included for more precise results.
Results: For better understanding of what role RNA molecules play in conferring cancer traits and how they can be reversed, more related studies are gathered here. In a study, it was revealed that lncRNA RNA H19 promotes tumor survival and metastasis by enabling resistance to chemotherapy. H19 overexpression in cisplatin-resistant SGC7901 cells correlates with elevated levels of miR-675 and suppressed expression of FADD, a critical apoptosis regulator. This disruption blocks caspase-8 and caspase-3 activation, allowing cancer cells to evade cell death. Importantly, silencing H19 in these cells reduces doxorubicin resistance, as evidenced by a lower IC50 value. In another study, it was explored how miR-200c-3p reverses cisplatin resistance in GC. It was found that miR-200c-3p levels were significantly reduced in SGC7901/DDP cells compared to their cisplatin-sensitive parental counterparts (SGC7901), while ERCC3 and ERCC4 protein levels were elevated. The findings suggested that miR-200c-3p acts as a key regulator of cisplatin resistance in GC by suppressing ERCC3 and ERCC4. Another example of RNA molecules that can play regulatory roles in cancer drug resistance are circular RNAs. A study revealed that circ-PVT1 is markedly overexpressed in both PTX-resistant GC tissues and cell lines. Silencing circ-PVT1 restored PTX sensitivity in resistant cells by acting as a molecular sponge for miR-124-3p, a microRNA that directly inhibits the EMT-promoting transcription factor ZEB1. Mechanistically, circ-PVT1 sequesters miR-124-3p, thereby upregulating ZEB1 expression and driving chemoresistance.
Based on RNA molecules' potential in epigenetic regulation, many therapeutic strategies have been designed. An intriguing approach is oligonucleotide-based therapies. Phase I trials of MG98, a DNMT1-targeting siRNA, showed partial responses in GC patients with platinum resistance. Preclinical studies combining MG98 with HDAC inhibitors demonstrated synergistic reactivation of tumor suppressor genes. RNA aptamers are also a group of therapeutic RNAs. Scientists have developed a dendrimer-based nanocarrier by conjugating the AS1411 aptamer to a polyamidoamine-polyethylene glycol complex to enhance the targeted delivery of 5-fluorouracil in GC. The AS1411 aptamer significantly improved 5-FU uptake in MKN45 GC cells through aptamer-mediated targeting. In vivo analyses revealed enhanced drug accumulation at tumor sites compared to non-targeted controls. Exosomal RNAs are another group of potent agents that are used to reverse resistance. In a study, exosomes loaded with si-c-Met (Exo-si-c-Met) efficiently downregulated c-Met expression in GC cells in vitro. This approach overcame cisplatin resistance, as evidenced by reduced IC50 values and restored apoptotic signaling. Silencing c-Met via siRNA (si-c-Met) significantly suppressed migration and invasion while inducing apoptosis in GC cells, demonstrating its potential to enhance cisplatin sensitivity. Critically, in vivo studies revealed that Exo-si-c-Met inhibited tumor growth by 65% compared to cisplatin alone in xenograft models.
Conclusion: RNA molecules are a group of versatile and easy-to-design tools in the process of epigenetic reprogramming, and can be of great help to combat drug-resistant GC. By efficiently targeting lncRNAs, miRNAs, and circRNAs, chemosensitivity can be restored and all the other characteristics of cancer (e.g., stemness, tumor microenvironment, etc.) can be reversed. It is true that RNA-based medications are the new generation of cancer therapy, but the delivery of these agents is still far from perfect. That is why further chemical modifications, tissue specific delivery systems, and many more aspects are in need of being addressed to achieve optimized outcomes.