METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis

作者：Jiashu Pan, Feng Liu, Xiaoli Xiao, Ruohui Xu, Liang Dai, Mingzhe Zhu, Hanchen Xu, Yangxian Xu, Aiguang Zhao, Wenjun Zhou, Yanqi Dang, Guang Ji · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2022 · DOI：10.1186/s13046-021-02227-8 · 被引用次数：105 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、Cancer-related gene regulation

BACKGROUND: Colorectal carcinoma (CRC) is the third most common cancer and second most common cause of cancer-related deaths worldwide. Ribonucleic acid (RNA) N6-methyladnosine (m6A) and methyltransferase-like 3 (METTL3) play key roles in cancer progression. However, the roles of m6A and METTL3 in CRC progression require further clarification. METHODS: Adenoma and CRC samples were examined to detect m6A and METTL3 levels, and tissue microarrays were performed to evaluate the association of m6A and METTL3 levels with the survival of patients with CRC. The biological functions of METTL3 were investigated through cell counting kit-8, wound healing, and transwell assays. M6A epitranscriptomic microarray, methylated RNA immunoprecipitation-qPCR, RNA stability, luciferase reporter, and RNA immunoprecipitation assays were performed to explore the mechanism of METTL3 in CRC progression. RESULTS: M6A and METTL3 levels were substantially elevated in CRC tissues, and patients with CRC with a high m6A or METTL3 levels exhibited shorter overall survival. METTL3 knockdown substantially inhibited the proliferation, migration, and invasion of CRC cells. An m6A epitranscriptomic microarray revealed that the cell polarity regulator Crumbs3 (CRB3) was the downstream target of METTL3. METTL3 knockdown substantially reduced the m6A level of CRB3, and inhibited the degradation of CRB3 mRNA to increase CRB3 expression. Luciferase reporter assays also showed that the transcriptional level of wild-ty...