N-methyladenosine enhances the expression of TGF-β-SMAD signaling family to inhibit cell growth and promote cell metastasis
TGF-β-SMAD signaling pathway plays an important role in the progression of various cancers. However, posttranscriptional regulation such as N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) 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 m<sup>6</sup>A-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 m<sup>6</sup>A 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.
Authors
- Yibi Zhang (ORCID: https://orcid.org/0000-0002-3232-9236)
- He Wang
- Tongfeng Liu
- Tianyou Cheng (ORCID: https://orcid.org/0000-0002-7012-520X)
- Liqiang Duan (ORCID: https://orcid.org/0000-0002-2566-1687)
- Xueqing Zhao (ORCID: https://orcid.org/0000-0003-1057-8458)
- Bo Peng (ORCID: https://orcid.org/0000-0001-5286-7413)
- Xijuan Yao (ORCID: https://orcid.org/0000-0003-1732-096X)
- Shan Gao (ORCID: https://orcid.org/0000-0003-0262-4549)
- Qingqing Zhang (ORCID: https://orcid.org/0000-0001-6296-7522)
- Yinmin Gu (ORCID: https://orcid.org/0000-0001-9825-5447)
- Jian Zeng (ORCID: https://orcid.org/0000-0002-4565-920X)
- Dalong Song (ORCID: https://orcid.org/0000-0002-9771-9577)
- Shuwen Cheng (ORCID: https://orcid.org/0009-0006-3402-6665)
- Xujie Zhao
- Xiaodong Wang (ORCID: https://orcid.org/0000-0003-3926-3505)
- Xuetong Wang (ORCID: https://orcid.org/0009-0002-2378-8585)
Institutions
- Shanghai University (CN)
- University of Science and Technology of China (CN)
- Guiyang Medical University (CN)
- Guizhou University (CN)
- Chinese Academy of Sciences (CN)
- Wenzhou Medical University (CN)
- Suzhou Institute of Biomedical Engineering and Technology (CN)
- Zhejiang Cancer Hospital (CN)
- Zhongda Hospital Southeast University (CN)
- Affiliated Hospital of Guizhou Medical University (CN)
- Shanxi Academy of Building Research (CN)
- Guizhou Provincial People's Hospital (CN)
- Nanjing Medical University (CN)
- Nanjing University (CN)
Publication Details
- Journal
- Cancer Letters
- Published
- 2024-08-31
- DOI
- https://doi.org/10.1016/j.canlet.2024.217195
- Citations
- 9
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.10
Funders
- National Natural Science Foundation of China
- Guizhou Science and Technology Department
- National University's Basic Research Foundation of China
- National Key Research and Development Program of China
- Fundamental Research Funds for the Central Universities
- National Key Research and Development Program of China Stem Cell and Translational Research