TRIM71 suppresses tumorigenesis via modulation of Lin28B-let-7-HMGA2 signaling.
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.
Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, Korea.|Specific Organs Cancer Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea.
Jinlong
J
Yin
Specific Organs Cancer Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea.
Tae-Hoon
TH
Kim
Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, Korea.|Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea.
Nayun
N
Park
Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, Korea.|Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea.
Daye
D
Shin
Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, Korea.|Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea.
Hae In
HI
Choi
Anticancer Agent Research Center, Korea Research Institute of Bioscience & Biotechnology, Ochang, Korea.
Sungchan
S
Cho
Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, Korea.|Specific Organs Cancer Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea.
Jong Bae
JB
Park
Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi, Korea.|Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea.
Jong Heon
JH
Kim
D000818:Animals; D018938:Caco-2 Cells; D063646:Carcinogenesis / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D025743:HMGA2 Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D041681:NIH 3T3 Cells; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000070584:Tripartite Motif Proteins / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
D025743:HMGA2 Protein; C516326:LIN28B protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D000070584:Tripartite Motif Proteins; C487931:mirnlet7 microRNA, human; C584142:TRIM71 protein, human; D044767:Ubiquitin-Protein Ligases
HMGA2; Lin28B; TRIM71; let-7; tumorigenesis