N-甲基腺苷增强TGF-β-SMAD信号家族的表达，抑制细胞生长，促进细胞转移。
N-methyladenosine enhances the expression of TGF-β-SMAD signaling family to inhibit cell growth and promote cell metastasis.
发表日期：2024 Aug 31
作者：
Bo Peng, Shuwen Cheng, He Wang, Tongfeng Liu, Yinmin Gu, Liqiang Duan, Tianyou Cheng, Xuetong Wang, Xiaodong Wang, Qingqing Zhang, Yibi Zhang, Xueqing Zhao, Xijuan Yao, Xujie Zhao, Dalong Song, Jian Zeng, Shan Gao
来源：
CANCER LETTERS
摘要：
TGF-β-SMAD信号通路在多种癌症的进展中发挥重要作用。然而，诸如 TGF-β-SMAD 信号轴的 N6-甲基腺苷 (m6A) 等转录后调节仍不完全清楚。在此，我们发现胰岛素样生长因子 2 mRNA 结合蛋白 2 (IGF2BP2) 低表达，与透明细胞肾细胞癌 (ccRCC) 患者的不良预后相关，并抑制 ccRCC 细胞的增殖并促进其转移。从机制上讲，IGF2BP2 通过以 m6A 依赖性方式介导 mRNA 稳定性，系统地调节 TGF-β-SMAD 信号家族，包括 TGF-β1/2、TGF-βR1/2 和 SMAD2/3/4。此外，IGF2BP2 对 ccRCC 细胞的功能作用是由 TGF-β-SMAD 信号传导下游效应器 SMAD4 介导的，该效应器在 5'UTR 和 CDS 中鉴定出三个 m6A 位点。我们的研究将 IGF2BP2-TGF-β-SMAD 轴确立为 ccRCC 中的新调节效应器，为开发新型治疗策略提供了新见解。版权所有 © 2024。由 Elsevier B.V. 出版。
TGF-β-SMAD signaling pathway plays an important role in the progression of various cancers. However, posttranscriptional regulation such as N6-methyladenosine (m6A) of TGF-β-SMAD signaling axis remains incompletely understood. Here, we reveal that insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) is low expression as well as associated with poor prognosis in clear cell renal cell carcinoma (ccRCC) patients and inhibits proliferation as well as promotes metastasis of ccRCC cells. Mechanistically, IGF2BP2 systematically regulates TGF-β-SMAD signaling family, including TGF-β1/2, TGF-βR1/2 and SMAD2/3/4, through mediating their mRNA stability in an m6A-dependent manner. Furthermore, the functional effects of IGF2BP2 on ccRCC cells is mediated by TGF-β-SMAD signaling downstream effector SMAD4, which is identified three m6A sites in 5'UTR and CDS. Our study establishes IGF2BP2-TGF-β-SMAD axis as a new regulatory effector in ccRCC, providing new insights for developing novel therapeutic strategies.Copyright © 2024. Published by Elsevier B.V.