Sun Meige, Zhang Xiaocui, Bi Fangfang, Wang Dandan, Zhou Xin, Li Xiao, Yang Qing
Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
Cancers (Basel). 2022 Oct 25;14(21):5218. doi: 10.3390/cancers14215218.
Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial ovarian cancer (EOC) development remains to be elucidated. In this study, the biological functions of FTO were verified in vitro and in vivo. The m6A modification and the binding sites of SNAI1 mRNA were confirmed by m6A RNA immunoprecipitation (MeRIP) and RIP experiments. The actinomycin D assay was used to test the stability of RNA. We found that FTO was downregulated with increased m6A levels in EOC. Reduced expression of FTO was associated with a higher FIGO stage in patients with EOC. Mechanistically, FTO decreased the m6A level and stability of SNAI1 mRNA, causing downregulation of SNAI1 and inhibiting epithelial-mesenchymal transition (EMT). Furthermore, FTO-mediated downregulation of SNAI1 expression depended on IGF2BP2, which acted as an m6A reader binding to the 3' UTR region of SNAI1 mRNA to promote its stability. In conclusion, FTO inhibits SNAI1 expression to attenuate the growth and metastasis of EOC cells in an m6A-IGF2BP2-dependent manner. Our findings suggest that the FTO-IGF2BP2-SNAI1 axis is a potential therapeutic target in EOC.
脂肪量与肥胖相关蛋白（FTO）在包括恶性肿瘤在内的多种疾病中调节关键通路。然而，FTO与其靶基因在上皮性卵巢癌（EOC）发生发展中的功能联系仍有待阐明。在本研究中，FTO的生物学功能在体外和体内得到验证。通过m6A RNA免疫沉淀（MeRIP）和RIP实验证实了SNAI1 mRNA的m6A修饰和结合位点。使用放线菌素D试验检测RNA的稳定性。我们发现EOC中FTO随着m6A水平升高而下调。FTO表达降低与EOC患者较高的国际妇产科联盟（FIGO）分期相关。机制上，FTO降低了SNAI1 mRNA的m6A水平和稳定性，导致SNAI1下调并抑制上皮-间质转化（EMT）。此外，FTO介导的SNAI1表达下调依赖于IGF2BP2，IGF2BP2作为一种m6A阅读蛋白，与SNAI1 mRNA的3'UTR区域结合以促进其稳定性。总之，FTO以m6A-IGF2BP2依赖的方式抑制SNAI1表达，从而减弱EOC细胞的生长和转移。我们的研究结果表明，FTO-IGF2BP2-SNAI1轴是EOC的一个潜在治疗靶点。
