B-crystallin complexes with 14-3-3 to induce epithelial-mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma
B-crystallin complexes with 14-3-3 to induce epithelial-mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma
复制标题
B-晶状体蛋白与 14-3-3 复合物诱导肝细胞癌上皮间质转化和索拉非尼耐药
DOI：
10.1002/hep.26255
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发表时间：
2013-06-01
期刊：
影响因子：
13.5
通讯作者：
Zhou, Jian
中科院分区：
文献类型：
--
作者：
Huang, Xiao-Yong;Ke, Ai-Wu;Zhou, Jian
肝细胞癌患者的总体存活率仍然较低，其分子发病机制仍未完全明确。在此，我们报告了B-晶体蛋白在人肝细胞癌中的高表达预示着低存活率和手术后的疾病复发。多变量分析确定B-晶体蛋白的表达是术后复发和总存活率的独立预测因子。我们发现在体内和体外，B-晶体蛋白的高表达促进了肝细胞癌的进展。我们证明，B-晶体蛋白的过度表达通过激活细胞外调节的蛋白激酶(ERK)级联通路，诱导肝癌细胞的上皮-间充质转化(EMT)，从而促进肝癌的进展，这可以抵消索拉非尼的作用。B-晶体蛋白与14-3-3蛋白结合并上调，导致ERK1/2活性上调。此外，B-Crystallin在肝癌细胞中的过表达通过ERK1/2/Fra-1/slug信号通路诱导EMT进展。临床上，我们的数据显示B-Crystallin和14-3-3的过度表达与肝细胞癌最差的生存结局相关，并且B-Crystallin过表达的患者的索拉非尼反应受损。结论：B-Crystallin-14-3-3复合体通过结构性激活ERK信号通路协同作用促进肝癌进展。这项研究揭示了B-晶体蛋白作为一种潜在的肝癌治疗靶点和预测索拉非尼治疗反应的生物标志物。(2013年《国际肝病》)
The overall survival of patients with hepatocellular carcinoma (HCC) remains poor, and the molecular pathogenesis remains incompletely defined in HCC. Here we report that increased expression of B-Crystallin in human HCC predicts poor survival and disease recurrence after surgery. Multivariate analysis identifies B-Crystallin expression as an independent predictor for postoperative recurrence and overall survival. We show that elevated expression of B-Crystallin promotes HCC progression in vivo and in vitro. We demonstrate that B-Crystallin overexpression fosters HCC progression by inducing epithelial-mesenchymal transition (EMT) in HCC cells through activation of the extracellular-regulated protein kinase (ERK) cascade, which can counteract the effect of sorafenib. B-Crystallin complexes with and elevates 14-3-3 protein, leading to up-regulation of ERK1/2 activity. Moreover, overexpression of B-Crystallin in HCC cells induces EMT progression through an ERK1/2/Fra-1/slug signaling pathway. Clinically, our data reveal that overexpression of both B-Crystallin and 14-3-3 correlates with the HCC poorest survival outcomes, and sorafenib response is impaired in patients with B-Crystallin overexpression. Conclusion: These data suggest that the B-Crystallin-14-3-3 complex acts synergistically to promote HCC progression by constitutively activating ERK signaling. This study reveals B-Crystallin as a potential therapeutic target for HCC and a biomarker for predicting sorafenib treatment response. (HEPATOLOGY 2013)