TRIM71 suppresses tumorigenesis via modulation of Lin28B-let-7-HMGA2 signaling.
TRIM71 suppresses tumorigenesis via modulation of Lin28B-let-7-HMGA2 signaling.
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DOI：
10.18632/oncotarget.13036
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发表时间：
2016-11-29
期刊：
影响因子：
--
通讯作者：
Kim JH
中科院分区：
文献类型：
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作者：
Yin J;Kim TH;Park N;Shin D;Choi HI;Cho S;Park JB;Kim JH
TRIM 71（tripartite motif-containing 71）属于TRIM-NHL蛋白家族，在调节早期发育和分化中起保守作用。然而，TRIM 71的分子功能在很大程度上仍然未知。在这里，我们探索了TRIM 71与Lin 28 B-let-7-HMGA 2（高迁移率族AT-钩2）信号传导的调节在肿瘤发生中的作用。TRIM 71过表达对抗Lin 28 B诱导的原代细胞转化，并抑制小鼠模型中的肿瘤形成。TRIM 71表达的特异性敲低增加癌细胞增殖和侵袭。相反，在Lin 28 B-let-7-HMGA 2信号传导保守的非小细胞肺癌（NSCLC）细胞中野生型TRIM 71的过表达降低了两种癌细胞表型。更重要的是，无论Lin 28 B-let-7-HMGA 2信号转导的保守状态如何，NSCLC细胞中泛素转移活性缺陷型TRIM 71突变体的过表达对增殖或侵袭没有影响。TRIM 71的致瘤抑制作用被TRIM 71下游靶标Lin 28 B和HMGA 2的过表达所拮抗。此外，生物信息学分析显示，TRIM 71表达在来自患者的各种类型的癌组织中下调。总之，这些数据表明TRIM 71通过转录后抑制Lin 28 B和随后调节肿瘤发生期间let-7-HMGA 2信号传导而起作用，从而潜在地起到肿瘤抑制剂的作用。
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.