N6-methyladenosine enhances the expression of TGF-β-SMAD signaling family to inhibit cell growth and promote cell metastasis

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2024-08-31 DOI:10.1016/j.canlet.2024.217195

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

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引用次数: 0

Abstract

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.

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N-甲基腺苷可增强 TGF-β-SMAD 信号家族的表达，从而抑制细胞生长并促进细胞转移。

TGF-β-SMAD 信号通路在各种癌症的进展过程中发挥着重要作用。然而，TGF-β-SMAD 信号轴的转录后调控（如 N6-甲基腺苷（m6A））仍不完全清楚。在这里，我们发现胰岛素样生长因子2 mRNA结合蛋白2（IGF2BP2）在透明细胞肾细胞癌（ccRCC）患者中低表达，且与不良预后相关，并能抑制ccRCC细胞的增殖和促进转移。从机理上讲，IGF2BP2 通过以 m6A 依赖性方式介导 TGF-β-SMAD（包括 TGF-β1/2、TGF-βR1/2 和 SMAD2/3/4）mRNA 的稳定性，系统地调节 TGF-β-SMAD 信号家族。此外，IGF2BP2对ccRCC细胞的功能影响是由TGF-β-SMAD信号转导下游效应物SMAD4介导的，该效应物在5'UTR和CDS中发现了三个m6A位点。我们的研究确定了IGF2BP2-TGF-β-SMAD轴是ccRCC的一个新的调控效应因子，为开发新型治疗策略提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.