title: Capn4 contributes to tumour growth and metastasis of hepatocellular carcinoma by activation of the FAK-Src signalling pathways.
abstract: Calpain small subunit 1 (Capn4) has been identified as a major gene that promotes metastasis of hepatocellular carcinoma (HCC). However, the mechanism by which Capn4 promotes progression of HCC is not understood. In this study, we found that Capn4 expression was increased in highly metastatic HCC cell lines and in tumour tissue from HCC patients compared to healthy patient tissue. Over-expression of Capn4 in HCC cells enhanced tumour cell growth in vitro and increased invasiveness, tumourigenicity and lung metastasis in vivo. Protein microarray analyses showed that expression of multiple proteins was regulated by Capn4. Interestingly, Capn4 was found to physically associate with FAK and promoted hyperactivity of the FAK-Src signalling pathway via increased phosphorylation of specific tyrosine residues of FAK, Src and p130Cas. Knock-down of Capn4 expression suppressed the malignant behaviour of HCC cells and inhibited the FAK-Src signalling pathway. Furthermore, Capn4-mediated invasion and metastasis of HCC cells required up-regulation of matrix metalloproteinase-2 (MMP2) through activation of this signalling pathway. Our clinical data revealed that Capn4 expression correlated well with the levels of phospho-FAK, and over-expression of both Capn4 and phospho-FAK correlates with the poorest survival outcomes in HCC. In conclusion, our data showed that Capn4 can contribute to HCC growth and metastasis via activation of the FAK-Src signalling pathway and MMP2.
authors: Liver Cancer Institute and Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, People's Republic of China.
authors: Zhi
authors: Z
authors: Dai
authors: Shao-Lai
authors: SL
authors: Zhou
authors: Zheng-Jun
authors: ZJ
authors: Zhou
authors: Dou-Sheng
authors: DS
authors: Bai
authors: Xiao-Yu
authors: XY
authors: Xu
authors: Xiu-Tao
authors: XT
authors: Fu
authors: Qing
authors: Q
authors: Chen
authors: Yi-Ming
authors: YM
authors: Zhao
authors: Kai
authors: K
authors: Zhu
authors: Lei
authors: L
authors: Yu
authors: Guo-Huan
authors: GH
authors: Yang
authors: Zheng
authors: Z
authors: Wang
authors: Wei-Zhong
authors: WZ
authors: Wu
authors: Jian
authors: J
authors: Zhou
authors: Jia
authors: J
authors: Fan
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D002154:Calpain / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D016016:Proportional Hazards Models; D015398:Signal Transduction / Q000502:physiology*; D046888:Tissue Array Analysis; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; D002154:Calpain; C527669:CAPNS1 protein, human
keywords: calpain small subunit 1; focal adhesion kinase; hepatocellular carcinoma; metastasis; prognosis