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TRIM71 suppresses tumorigenesis via modulation of Lin28B-let-7-HMGA2 signaling

2016; Impact Journals LLC; Volume: 7; Issue: 48 Linguagem: Inglês

10.18632/oncotarget.13036

1949-2553

Jinlong Yin, Taehoon Kim, Nayun Park, Daye Shin, Hae In Choi, Sungchan Cho, Jong Bae Park, Jong Heon Kim,

Circular RNAs in diseases

// Jinlong Yin 1, 3 , Tae-Hoon Kim 3 , Nayun Park 1, 2 , Daye Shin 1, 2 , Hae In Choi 1, 2 , Sungchan Cho 4 , Jong Bae Park 1, 3 , Jong Heon Kim 1, 2 1 Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, Korea 2 Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea 3 Specific Organs Cancer Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea 4 Anticancer Agent Research Center, Korea Research Institute of Bioscience & Biotechnology, Ochang, Korea Correspondence to: Jong Heon Kim, email: jhkim@ncc.re.kr Jong Bae Park, email: jbp@ncc.re.kr Keywords: TRIM71, Lin28B, let-7, HMGA2, tumorigenesis Received: September 16, 2016 Accepted: October 14, 2016 Published: November 03, 2016 ABSTRACT TRIM71 (tripartite motif-containing 71) belongs to the TRIM-NHL protein family, which plays a conserved role in regulating early development and differentiation. However, the molecular functions of TRIM71 have remained largely unknown. Here, we explored the role of TRIM71 together with modulation of Lin28B-let-7-HMGA2 (high-mobility group AT-hook 2) signaling in tumorigenesis. TRIM71 overexpression opposed Lin28B-induced transformation in primary cells and inhibited tumor formation in a mouse model. Specific knockdown of TRIM71 expression increased cancer cell proliferation and invasion. Conversely, overexpression of wild-type TRIM71 in non-small cell lung carcinoma (NSCLC) cells in which Lin28B-let-7-HMGA2 signaling was conserved decreased both cancer cell phenotypes. More importantly, overexpression of an ubiquitin transfer activity-deficient TRIM71 mutant in NSCLC cells had no effect on proliferation or invasion, regardless of the conservation status of Lin28B-let-7-HMGA2 signaling. The tumorigenic inhibitory action of TRIM71 was antagonized by overexpression of the TRIM71 downstream targets, Lin28B and HMGA2. Furthermore, a bioinformatics analysis revealed that TRIM71 expression was downregulated in various types of cancer tissue from patients. Taken together, these data indicate that TRIM71 acts through post-transcriptional repression of Lin28B and subsequent modulation of let-7-HMGA2 signaling during tumorigenesis to potentially function as a tumor suppressor.