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.
Keywords: HMGA2; Lin28B; TRIM71; let-7; tumorigenesis.