Chen Xiao-Yu, Yang Yan-Ling, Yu Yi, Chen Zhao-Yu, Fan Hui-Ning, Zhang Jing, Zhu Jin-Shui
Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
Pharmacol Res. 2024 Jun;204:107206. doi: 10.1016/j.phrs.2024.107206. Epub 2024 May 9.
Chemoresistance is a major therapeutic challenge in advanced gastric cancer (GC). N-methyladenosine (mA) RNA modification has been shown to play fundamental roles in cancer progression. However, the underlying mechanisms by which mA modification of circRNAs contributes to GC and chemoresistance remain unknown. We found that hsa_circ_0030632 (circUGGT2) was a predominant mA target of METTL14, and METTL14 knockdown (KD) reduced circUGGT2 mA 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 mA modification of circUGGT2 inhibits GC progression and DDP resistance by regulating miR-186-3p/MAP3K9 axis.
化疗耐药是晚期胃癌（GC）治疗中的一项重大挑战。N-甲基腺苷（mA）RNA修饰已被证明在癌症进展中发挥着重要作用。然而，circRNAs的mA修饰促进GC和化疗耐药的潜在机制仍不清楚。我们发现hsa_circ_0030632（circUGGT2）是METTL14的主要mA靶点，敲低（KD）METTL14可降低circUGGT2的mA水平，但增加其mRNA水平。circUGGT2在顺铂（DDP）耐药的GC细胞中表达明显增加。circUGGT2基因敲除在体外和体内均损害细胞生长、转移和DDP耐药性，但circUGGT2过表达则促进这些作用。此外，circUGGT2被证实可吸附miR-186-3p并上调MAP3K9，并且可以消除METTL14导致的GC细胞中miR-186-3p上调和MAP3K9下调。circUGGT2与miR-186-3p表达呈负相关，并且在GC患者中预后较差。我们的研究结果揭示，METTL14依赖的circUGGT2的mA修饰通过调节miR-186-3p/MAP3K9轴抑制GC进展和DDP耐药。
