Wang Bo, Wang Yuting, Wang Wantong, Wang Zihao, Zhang Yunzheng, Pan Xin, Wen Xin, Leng Hongrui, Guo Jing, Ma Xiao-Xin
Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang City, Liaoning Province, 110022, China.
J Exp Clin Cancer Res. 2024 Jul 23;43(1):204. doi: 10.1186/s13046-024-03120-w.
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.
子宫内膜癌（EC）干细胞（ECSCs）在EC的肿瘤发生、转移、免疫逃逸、化疗耐药及复发过程中起关键作用。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，WTAP和m6A水平在EC和ECSCs中均降低，敲低WTAP可促进ECCs和ECSCs的特性，包括增殖、侵袭、迁移、顺铂耐药及自我更新。WTAP的下调导致EGR1 mRNA的m6A修饰减少，作为m6A阅读器的IGF2BP3难以识别并结合失去m6A修饰的EGR1 mRNA，导致EGR1 mRNA稳定性降低。EGR1水平降低导致肿瘤抑制基因PTEN表达减少，导致细胞稳态失调和丧失，从而促进EC干细胞特征。值得注意的是，WTAP、EGR1和PTEN的强制过表达在体内抑制了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力。我们的研究结果表明，WTAP/EGR1/PTEN途径是EC干细胞维持、化疗耐药和肿瘤发生的重要调节因子，为EC治疗提供了一条新的、有前景的治疗途径。
