Translationally controlled tumor protein induces mitotic defects and chromosome missegregation in hepatocellular carcinoma development
Translationally controlled tumor protein induces mitotic defects and chromosome missegregation in hepatocellular carcinoma development
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DOI：
10.1002/hep.24709
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发表时间：
2012-02-01
期刊：
影响因子：
13.5
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Chan, Tim Hon Man;Chen, Leilei;Guan, Xin-Yuan
越来越多的证据表明，染色域解旋酶/ATPase DNA结合蛋白1样基因(CHD1L)是人肝细胞癌中的一种特异性癌基因。为了更好地了解携带CHD1L扩增的肝细胞癌(>；50%肝细胞癌)的分子机制，我们确定了CHD1L靶点，翻译控制的肿瘤蛋白(TCTP)，并研究了它在肝细胞癌进展中的作用。在这里，我们报告CHD1L蛋白直接与TCTP的启动子区域(NT-733至-1,027)结合并激活TCTP转录。在40.7%的人肝细胞癌标本中检测到TCTP的过表达，并与CHD1L的过表达呈正相关。在临床上，TCTP的过表达与肝癌患者的晚期(P=0.037)和总生存期(P=0.034)显著相关。在多变量分析中，TCTP被确定为与不良预后相关的独立标记物。小鼠体内和体外功能研究表明，TCTP具有致瘤作用，CHD1L诱导的TCTP过表达导致肿瘤细胞有丝分裂缺陷。进一步的机制研究表明，TCTP促进了有丝分裂过程中CDc25C泛素-蛋白酶体的降解，导致Tyr15上CDK1的去磷酸化失败，降低了CDK1的活性。因此，有丝分裂中CDK1活性的突然下降导致有丝分裂更快退出和染色体错误分离，从而导致染色体不稳定。耗竭实验证明，TCTP的致瘤性与其在有丝分裂缺陷中的作用有关。结论：我们共同揭示了一个新的分子途径(CHD1L/TCTP/CDC25C/CDK1)，它导致肝细胞的恶性转化，其表型为有丝分裂加速和产生非整倍体。(2012国际肝病)
Emerging evidence implicates the chromodomain helicase/ATPase DNA binding protein 1like gene (CHD1L) as a specific oncogene in human hepatocellular carcinoma (HCC). To better understand the molecular mechanisms underlying HCC cases carrying CHD1L amplification (>50% HCCs), we identified a CHD1L target, translationally controlled tumor protein (TCTP), and investigated its role in HCC progression. Here, we report that CHD1L protein directly binds to the promoter region (nt -733 to -1,027) of TCTP and activates TCTP transcription. Overexpression of TCTP was detected in 40.7% of human HCC samples analyzed and positively correlated with CHD1L overexpression. Clinically, overexpression of TCTP was significantly associated with the advanced tumor stage (P = 0.037) and overall survival time of HCC patients (P = 0.034). In multivariate analyses, TCTP was determined to be an independent marker associated with poor prognostic outcomes. In vitro and in vivo functional studies in mice showed that TCTP has tumorigenic abilities, and overexpression of TCTP induced by CHD1L contributed to the mitotic defects of tumor cells. Further mechanistic studies demonstrated that TCTP promoted the ubiquitin-proteasome degradation of Cdc25C during mitotic progression, which caused the failure in the dephosphorylation of Cdk1 on Tyr15 and decreased Cdk1 activity. As a consequence, the sudden drop of Cdk1 activity in mitosis induced a faster mitotic exit and chromosome missegregation, which led to chromosomal instability. The depletion experiment proved that the tumorigenicity of TCTP was linked to its role in mitotic defects. Conclusion: Collectively, we reveal a novel molecular pathway (CHD1L/TCTP/Cdc25C/Cdk1), which causes the malignant transformation of hepatocytes with the phenotypes of accelerated mitotic progression and the production of aneuploidy. (HEPATOLOGY 2012)