title: αB-crystallin complexes with 14-3-3ζ to induce epithelial-mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma.
abstract: 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.
  
  
  CONCLUSIONS
  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. (HEPATOLOGY 2013).
authors: Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, PR China.
authors: Xiao-Yong
authors: XY
authors: Huang
authors: Ai-Wu
authors: AW
authors: Ke
authors: Guo-Ming
authors: GM
authors: Shi
authors: Xin
authors: X
authors: Zhang
authors: Chi
authors: C
authors: Zhang
authors: Ying-Hong
authors: YH
authors: Shi
authors: Xiao-Ying
authors: XY
authors: Wang
authors: Zhen-Bin
authors: ZB
authors: Ding
authors: Yong-Sheng
authors: YS
authors: Xiao
authors: Jun
authors: J
authors: Yan
authors: Shuang-Jian
authors: SJ
authors: Qiu
authors: Jia
authors: J
authors: Fan
authors: Jian
authors: J
authors: Zhou
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D040901:Proteomics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D000077157:Sorafenib; D014157:Transcription Factors / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000378:metabolism*; D000099169:Fos-Related Antigen 1
chemical_list: D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D009536:Niacinamide; D010671:Phenylurea Compounds; D016760:Proto-Oncogene Proteins c-fos; D000071250:Snail Family Transcription Factors; D000077157:Sorafenib; D014157:Transcription Factors; D038203:alpha-Crystallin B Chain; D000099169:Fos-Related Antigen 1; C000604407:SNAI1 protein, human; C572235:YWHAZ protein, human