子宫内膜癌(EC)干细胞(ECSCs)在肿瘤发生过程中起着重要作用,转移,免疫逃逸,化学抗性,和EC的复发。然而,EC细胞(ECCs)中干细胞维持的具体机制尚未阐明.我们发现在EC和ECSCs中WTAP和m6A水平均下降,击倒WTAP促进了ECCs和ECSCs的属性,包括扩散,入侵,迁移,顺铂耐药,和自我更新。WTAP的下调导致EGR1mRNA的m6A修饰减少,对于IGF2BP3来说,作为M6A阅读器,识别并结合已经失去m6A修饰的EGR1mRNA,导致EGR1mRNA的稳定性降低。EGR1水平的降低导致抑癌基因PTEN表达的降低,导致细胞稳态失调和丧失,从而促进EC干细胞性状。值得注意的是,WTAP的强制过度表达,EGR1和PTEN在体内抑制ECCs和ECSCs的致癌作用,WTAP+EGR1和EGR1+PTEN的联合过表达进一步降低了这些细胞的致瘤潜能。我们的发现揭示WTAP/EGR1/PTEN通路是EC干细胞维持的重要调节因子,化疗抗性,和肿瘤发生,提出了一种新颖且有前途的治疗EC的方法。
Endometrial cancer (EC) stem cells (ECSCs) are pivotal in the oncogenesis, metastasis, immune escape, chemoresistance, and recurrence of EC. However, the specific mechanism of stem cell maintenance in EC cells (ECCs) has not been clarified. We found that WTAP and m6A levels decreased in both EC and ECSCs, and that knocking down WTAP promoted ECCs and ECSCs properties, including proliferation, invasion, migration, cisplatin resistance, and self-renewal. The downregulation of WTAP leads to a decrease in the m6A modification of EGR1 mRNA, and it is difficult for IGF2BP3, as an m6A reader, to recognize and bind to EGR1 mRNA that has lost m6A modification, resulting in a decrease in the stability of EGR1 mRNA. A decrease in the EGR1 level led to a decrease of in the expression tumor suppressor gene PTEN, resulting in deregulation and loss of cellular homeostasis and thereby fostering EC stem cell traits. Notably, the enforced overexpression of WTAP, EGR1, and PTEN inhibited the oncogenic effects of ECCs and ECSCs in vivo, and the combined overexpression of WTAP + EGR1 and EGR1 + PTEN further diminished the tumorigenic potential of these cells. Our findings revealed that the WTAP/EGR1/PTEN pathway is important regulator of EC stem cell maintenance, chemotherapeutic resistance, and tumorigenesis, suggesting a novel and promising therapeutic avenue for treating EC.