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Chemoresistance is a major therapeutic challenge in advanced gastric cancer (GC). N 6 -methyladenosine (m 6 A) RNA modification has been shown to play fundamental roles in cancer progression. However, the underlying mechanisms by which m 6 A modification of circRNAs contributes to GC and chemoresistance remain unknown. We found that hsa_circ_0030632 (circUGGT2) was a predominant m 6 A target of METTL14, and METTL14 knockdown (KD) reduced circUGGT2 m 6 A levels but increased its mRNA levels. The expression of circUGGT2 was markedly increased in cisplatin (DDP)-resistant GC cells. CircUGGT2 KD impaired cell growth, metastasis and DDP-resistance in vitro and in vivo, but circUGGT2 overexpression prompted these effects. Furthermore, circUGGT2 was validated to sponge miR-186-3p and upregulate MAP3K9 and could abolish METTL14-caused miR-186-3p upregulation and MAP3K9 downregulation in GC cells. circUGGT2 negatively correlated with miR-186-3p expression and harbored a poor prognosis in patients with GC. Our findings unveil that METTL14-dependent m 6 A modification of circUGGT2 inhibits GC progression and DDP resistance by regulating miR-186-3p/MAP3K9 axis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and purpose: The current treatment of ovarian cancer is surgery and adjuvant platinum-based chemotherapy. However, relapse and drug resistance are common. We have demonstrated the platelet-activating factor receptor (PAFR) is highly expressed in epithelial ovarian cancer, promoting ovarian cancer cell proliferation and invasion. The objective was to explore the effect of PAFR expression on cisplatin (CDDP) in ovarian cancer cells to provide novel theoretical basis for ovarian cancer therapy. Methods: The upregulation of PAFR in CDDP-treated ovarian cancer cells was observed using Western blot and real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR). The role of nuclear factor Kappa-B (NF-κB)/p65 and hypoxia inducible factor-1α (HIF-1α) in modulating PAFR expression was assessed using Western blot, siRNA and immunofluorescence. The effect of PAFR on CDDP sensitivity was observed using a pharmacological inhibitor and siRNA knockdown. Results: CDDP induced dose- and timedependent upregulation of PAFR in two ovarian cancer cell lines (P<0.01). The downregulation of PAFR by CDDP correlated with the inhibitions of NF-κB and HIF-1α which were accumulated by CDDP in the nucleus. Inhibition of PAFR expression by PAFR specific small molecule antagonist WEB2086 or RNA interference could significantly improve the sensitivity of ovarian cancer cells to CDDP. The cell proliferation ability decreased significantly (P<0.01), while the apoptotic rate increased significantly (P<0.01). Increased expression of PAFR activated downstream AKT and ERK pathways in CDDP-treated cells. Conclusion: CDDP induces upregulation of PAFR by accumulating NF-κB and HIF-1α in the nucleus. PAFR inhibition may modulate the CDDP sensitivity in ovarian cancer cells, which is a novel and promising therapeutic target for sensitizing ovarian cancer cells to CDDP. [ABSTRACT FROM AUTHOR]