Department of Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Gynecology, Yiwu Central Hospital, Yiwu, Zhejiang, China.
Lab Invest. 2021 Jun;101(6):775-784. doi: 10.1038/s41374-021-00543-3. Epub 2021 Mar 10.
Dysregulation of long noncoding RNA (LncRNA) FENDDR has been shown to be closely related to the progression of several cancers. However, its role and upstream regulatory mechanism in endometrioid endometrial carcinoma (EEC) remains unclear. This study was conducted using the cancerous tissues of EEC patients (n = 60), EEC cell lines, and a xenograft mouse model. The expression level of LncRNA FENDRR was decreased and the N-methyladenosine (m6A) methylation levels of LncRNA FENDRR was elevated in cancerous tissues of EEC patients. In vitro experiments demonstrated that YTH domain-containing 2 (YTHDF2), an m6A reader, recognized the abundance of m6A-modified LncRNA FENDRR in EEC cells and promoted its degradation. LncRNA FENDRR overexpression suppressed cell proliferation and facilitated cell apoptosis in the EEC cell line HEC-1B by reducing the protein level of SRY-related HMG box transcription factor 4 (SOX4). Interference of LncRNA FENDRR reversed the inhibitory effect of sh-YTHDF2 on cell proliferation and the promoting effect of sh-YTHDF2 on cell apoptosis in HEC-1B cells by silencing FENDRR. Finally, in vivo experiments confirmed that overexpression of LncRNA FENDRR retarded the growth of EEC cells. In conclusion, YTHDF2-mediated LncRNA FENDRR degradation promotes cell proliferation by elevating SOX4 expression in EEC.
长链非编码 RNA (LncRNA) FENDRR 的失调已被证明与几种癌症的进展密切相关。然而，其在子宫内膜样型子宫内膜癌 (EEC) 中的作用和上游调控机制尚不清楚。本研究使用 EEC 患者的癌组织（n=60）、EEC 细胞系和异种移植小鼠模型进行。EEC 患者癌组织中 LncRNA FENDRR 的表达水平降低，LncRNA FENDRR 的 N-甲基腺苷（m6A）修饰水平升高。体外实验表明，m6A 阅读蛋白 YTH 结构域包含蛋白 2（YTHDF2）识别 EEC 细胞中 m6A 修饰的 LncRNA FENDRR 的丰度，并促进其降解。LncRNA FENDRR 过表达通过降低 SRY 相关 HMG 盒转录因子 4（SOX4）的蛋白水平，抑制 EEC 细胞系 HEC-1B 中的细胞增殖并促进细胞凋亡。LncRNA FENDRR 的干扰通过沉默 FENDRR 逆转了 sh-YTHDF2 对 HEC-1B 细胞中细胞增殖的抑制作用和对细胞凋亡的促进作用。最后，体内实验证实 LncRNA FENDRR 的过表达可延缓 EEC 细胞的生长。总之，YTHDF2 介导的 LncRNA FENDRR 降解通过提高 EEC 中 SOX4 的表达促进细胞增殖。
