Abstract 4069: Capn4 contributes to tumor growth and metastasis of hepatocellular carcinoma by activation of FAK-Src signaling pathways

Abstract

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 tumor tissue from HCC patients compared to healthy patient tissue. Overexpression of Capn4 in HCC cells enhanced tumor cell growth in vitro and increased invasiveness, tumorigenicity, and lung metastasis in vivo. Protein microarray analyses in HCC cells with altered Capn4 levels (through Capn4 silencing or overexpression) showed that expression of multiple proteins was regulated by Capn4 and that the activation of focal adhesion kinase (FAK) signaling pathways might play a key role in Capn4-enhanced tumor development. Immunoprecipitation and western blotting verified that Capn4 was physically associated with FAK and promoted hyperactivity of the FAK-Src signaling pathway via increased phosphorylation of specific tyrosine residues of FAK, Src, and p130Cas. Knockdown of Capn4 expression suppressed the malignant behavior of HCC cells and inhibited the FAK-Src signaling pathway. Furthermore, Capn4-mediated invasion and metastasis of HCC cells required up-regulation of matrix metalloproteinase-2 (MMP2) through activation of this signaling pathway. Our clinical data revealed that Capn4 expression correlated well with the levels of phospho-FAK, and overexpression of both Capn4 and phospho-FAK correlates with the poorest survival outcomes in HCC. These results suggest that Capn4 can contribute to HCC growth and metastasis via activation of the FAK-Src Signaling pathway and MMP2. Capn4 could be a therapeutic target for HCC. Citation Format: Zhi Dai, Jian Zhou, Jia Fan. Capn4 contributes to tumor growth and metastasis of hepatocellular carcinoma by activation of FAK-Src signaling pathways. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4069. doi:10.1158/1538-7445.AM2014-4069