Journal
MOLECULAR ONCOLOGY
Volume 13, Issue 12, Pages 2663-2678Publisher
WILEY
DOI: 10.1002/1878-0261.12581
Keywords
lung cancer; miR-195; miR-497; SMURF2; Transforming growth factor (TGF)-beta
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Funding
- Korea Government (MSIP) [NRF-2019R1A2C2004052]
- R&D Convergence Program of NST (National Research Council of Science & Technology) of Republic of Korea [CAP-16-03-KRIBB]
- Korea Institute of Science and Technology [2E28030]
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SMURF2 is a member of the HECT family of E3 ubiquitin ligases that have important roles as a negative regulator of transforming growth factor-beta (TGF-beta) signaling through ubiquitin-mediated degradation of TGF-beta receptor I. However, the regulatory mechanism of SMURF2 is largely unknown. In this study, we identified that micro(mi)R-195 and miR-497 putatively target SMURF2 using several target prediction databases. Both miR-195 and miR-497 bind to the 3 '-UTR of the SMURF2 mRNA and inhibit SMURF2 expression. Furthermore, miR-195 and miR-497 regulate SMURF2-dependent T beta RI ubiquitination and cause the activation of the TGF-beta signaling pathway in lung cancer cells. Upregulation of miR-195 and miR-497 significantly reduced cell viability and colony formation through the activation of TGF-beta signaling. Interestingly, miR-195 and miR-497 also reduced the invasion ability of lung cancer cells when cells were treated with TGF-beta 1. Subsequent in vivo studies in xenograft nude mice model revealed that miR-195 and miR-497 repress tumor growth. These findings demonstrate that miR-195 and miR-497 act as a tumor suppressor by suppressing ubiquitination-mediated degradation of TGF-beta receptors through SMURF2, and suggest that miR-195 and miR-497 are potential therapeutic targets for lung cancer.
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