Background Chemoresistance is a major therapeutic challenge in advanced gastric cancer (GC). N6-methyladenosine (m6A) RNA modification has been shown to play fundamental roles in cancer progression. However, the underlying mechanisms by which m6A modification of circRNAs contributes to GC and chemoresistance remain unknown.

Methods Through m6A-circRNA epitranscriptome microarray screening and RNA immunoprecipitation (RIP) analysis, we identified the influence of METTL14 on the m6A modification of circUGGT2 in cisplatin (DDP)-resistant GC cells, we analyzed its role in GC. Through in vivo and in vitro studies of the knockout and overexpression of circUGGT2, we investigated its effects on cell growth, migration, and DDP resistance. We further explored the relationship between circUGGT2 and miR-186-3p and its regulation of MAP3K9. Finally, we analyzed clinical data to assess the prognostic value of circUGGT2 in GC patients.

Results We found that hsa_circ_0030632 (circUGGT2) was a predominant m6A target of METTL14, and METTL14 knockdown (KD) reduced circUGGT2 m6A 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 (IDDF2024-ABS-0272 Figure1).

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Abstract IDDF2024-ABS-0272 Figure 1

Conclusions Our findings unveil that METTL14-dependent m6A modification of circUGGT2 inhibits GC progression and DDP-resistance by regulating miR-186-3p/MAP3K9 axis.