METTL14-dependent m 6 A modification of circUGGT2 drives gastric cancer progression by sponging miR-186-3p and upregulating MAP3K9

Abstract Background: N6-methyladenosine (m6A) RNA modification has been shown to act fundamental roles in cancer progression. However, the underlying mechanisms by which m6A modification of circRNAs contributes to gastric cancer (GC) remain unknown. Methods: METTL14-mediated m6A modification of circRNAs was identified by an m6A-circRNA epi-transcriptomic microarray and verified by methylated RNA immunoprecipitation (MeRIP) and m6A dot blot. Cell bio-behaviors were measured by molecular oncology experiments in vitro and in vivo. The mechanisms underlying gastric tumorigenesis were conducted by RIP, luciferase gene report, RT-qPCR. and Western blot analyses. The prognostic significance was analyzed by FISH and TCGA dataset. 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. circUGGT2 KD impaired cell growth and metastasis 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. Conclusion: Our findings unveil that METTL14-dependent m6A modification of circUGGT2 promotes GC progression by sponging miR-186-3p and upregulating MAP3K9.