Wu Huili, Chu Feifei, Li Lu, Li Kunkun, Xiao Xingguo, Zhang Li, Zhang Yong
Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China.
Medical Key Laboratory of Diagnosis and Treatment of Colorectal Cancer in Henan Province, Zhengzhou 450007, China.
J Oncol. 2022 Dec 15;2022:1600611. doi: 10.1155/2022/1600611. eCollection 2022.
N6-methyladenosine (m6A) modification plays a crucial role in determining the fate and function of RNA transcripts in tumor cells. Nevertheless, how m6A regulates the expression of key molecules and coordinates its involvement in the development of colorectal cancer (CRC) remains largely unclear. Here, we report that the m6A reading protein YTHDF1-mediated up-regulation of SH3TC2 promotes CRC growth both in vitro and in vivo. In a pan-cancer analysis across more than thirty types of cancer, we found that SH3TC2 was dysregulated in nine cancers, including BLCA, CHOL, COAD, LAML, PAAD, READ, SKCM, BRCA, and TGCT, and was closely associated with patient prognosis in four cancers, including COAD, MESO, PAAD, and READ. In particular, SH3TC2 was overexpressed in CRC as confirmed by six independent study cohorts. Clinically, high expression of SH3TC2 predicted worse disease-free survival (DFS) in CRC patients. SH3TC2 showed fascinating diagnostic value and was correlated with immunosuppression in CRC. Functionally, RNA-sequencing combined with experiments revealed that knockdown of SH3TC3 significantly inhibited cell-cycle progress of CRC, impairing cell growth. Mechanistically, YTHDF1 protein directly binds with SH3TC2 mRNA and promotes its elevation in an m6A-dependent manner. Thus, our findings provide a mechanism to target the YTHDF1/SH3TC2 axis for CRC therapy.
N6-甲基腺苷（m6A）修饰在决定肿瘤细胞中RNA转录本的命运和功能方面起着关键作用。然而，m6A如何调节关键分子的表达并协调其在结直肠癌（CRC）发生发展中的作用在很大程度上仍不清楚。在此，我们报告m6A阅读蛋白YTHDF1介导的SH3TC2上调在体外和体内均促进CRC生长。在对三十多种癌症的泛癌分析中，我们发现SH3TC2在包括膀胱癌（BLCA）、胆管癌（CHOL）、结肠癌（COAD）、急性髓系白血病（LAML）、胰腺癌（PAAD）、直肠癌（READ）、皮肤黑色素瘤（SKCM）、乳腺癌（BRCA）和睾丸生殖细胞肿瘤（TGCT）在内的九种癌症中表达失调，并且在包括COAD、间皮瘤（MESO）、PAAD和READ在内的四种癌症中与患者预后密切相关。特别是，六项独立研究队列证实SH3TC2在CRC中过表达。临床上，SH3TC2高表达预示CRC患者无病生存期（DFS）较差。SH3TC2具有出色的诊断价值，并且与CRC中的免疫抑制相关。在功能上，RNA测序结合实验表明，敲低SH3TC3可显著抑制CRC的细胞周期进程，损害细胞生长。机制上，YTHDF1蛋白直接与SH3TC2 mRNA结合，并以m6A依赖的方式促进其表达升高。因此，我们的研究结果提供了一种针对YTHDF1/SH3TC2轴进行CRC治疗的机制。
