Role of claudin-1 in hepatocellular carcinoma cell invasion

Abstract

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, and is currently the third-leading cause of cancer death among men in Asia and Africa. The invasiveness of HCC has become a major obstacle to better prognosis and a major target for researchers. Claudins (CLD) are recently identified members of the tetraspanin family of proteins, which are integral to the structure and function of TJs. Recent studies showed changes in expression of CLDs during tumorigenesis. However, a causal relationship between CLD expression and cancer has not been established. In this study, we show that CLD1 plays a crucial role in HCC cell invasion. siRNA targeting of CLD1 completely inhibited HCC cell invasion. Conversely, CLD1 disturbs cell-cell adhesion, and induced invasive behavior in normal liver cells. We also found downregulation of β-catenin and loss of E-cadherin in cells expressing CLD, resulting in loss of cell-cell adhesion. c-Abl-PKC-delta signaling pathway was selectively involved in loss of cell-cell adhesion and cellular invasion in response to CLD1 expression. The present observations raise the possibility of exploiting CLD1 as a potential biomarker for liver cancer progression and might provide new opportunities for therapeutic intervention.