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αB‐crystallin complexes with 14‐3‐3ζ to induce epithelial‐mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma
Author(s) -
Huang XiaoYong,
Ke AiWu,
Shi GuoMing,
Zhang Xin,
Zhang Chi,
Shi YingHong,
Wang XiaoYing,
Ding ZhenBin,
Xiao YongSheng,
Yan Jun,
Qiu ShuangJian,
Fan Jia,
Zhou Jian
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26255
Subject(s) - sorafenib , epithelial–mesenchymal transition , hepatocellular carcinoma , cancer research , mapk/erk pathway , downregulation and upregulation , kinase , signal transduction , medicine , biology , oncology , cancer , metastasis , microbiology and biotechnology , biochemistry , gene
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 αB‐Crystallin in human HCC predicts poor survival and disease recurrence after surgery. Multivariate analysis identifies αB‐Crystallin expression as an independent predictor for postoperative recurrence and overall survival. We show that elevated expression of αB‐Crystallin promotes HCC progression in vivo and in vitro . We demonstrate that αB‐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. αB‐Crystallin complexes with and elevates 14‐3‐3ζ protein, leading to up‐regulation of ERK1/2 activity. Moreover, overexpression of αB‐Crystallin in HCC cells induces EMT progression through an ERK1/2/Fra‐1/slug signaling pathway. Clinically, our data reveal that overexpression of both αB‐Crystallin and 14‐3‐3ζ correlates with the HCC poorest survival outcomes, and sorafenib response is impaired in patients with αB‐Crystallin overexpression. Conclusion: These data suggest that the αB‐Crystallin‐14‐3‐3ζ complex acts synergistically to promote HCC progression by constitutively activating ERK signaling. This study reveals αB‐Crystallin as a potential therapeutic target for HCC and a biomarker for predicting sorafenib treatment response. (H EPATOLOGY 2013)