MiR‐195 and miR‐497 suppress tumorigenesis in lung cancer by inhibiting SMURF2‐induced TGF‐β receptor I ubiquitination

• Published in: Molecular oncology Vol. 13; no. 12; pp. 2663 - 2678
• Main Authors: Chae, Dong‐Kyu, Park, Jinyoung, Cho, Moonsoo, Ban, Eunmi, Jang, Mihue, Yoo, Young Sook, Kim, Eunice EunKyeong, Baik, Ja‐Hyun, Song, Eun Joo
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.12.2019; John Wiley and Sons Inc; Wiley
• Subjects: Apoptosis; Breast cancer; Cell cycle; Cell growth; Cell viability; Gene expression; Growth factors; Health aspects; Ligases; Lung cancer; Metastasis; MicroRNAs; miR‐195; miR‐497; mRNA; Penicillin; RNA; Roles; Signal transduction; SMURF2; Studies; Therapeutic applications; Transforming growth factor (TGF)‐β; Transforming growth factor-b; Transforming growth factor-b1; Transforming growth factors; Tumor suppressor genes; Tumorigenesis; Tumors; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Xenografts; South Korea; United States > US; lung cancer; miR-195; Transforming growth factor (TGF)-β; SMURF2; miR-497
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12581

SMURF2 is a member of the HECT family of E3 ubiquitin ligases that have important roles as a negative regulator of transforming growth factor‐β (TGF‐β) signaling through ubiquitin‐mediated degradation of TGF‐β 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 TβRI ubiquitination and cause the activation of the TGF‐β 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‐β signaling. Interestingly, miR‐195 and miR‐497 also reduced the invasion ability of lung cancer cells when cells were treated with TGF‐β1. 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‐β receptors through SMURF2, and suggest that miR‐195 and miR‐497 are potential therapeutic targets for lung cancer. We demonstrated that ectopic expression of miR‐195 and miR‐497 by mimics suppressed TβR1 ubiquitination and degradation through the repression of SMURF2. These results suggest that the reduction of SMURF2 gene expression by miR‐195 or miR‐497, which results in activation of transforming growth factor‐β signaling, has an important role in inhibiting lung cancer.