Inhibition of hepatocellular carcinoma invasion by suppression of claudin-10 in HLE cells.

Abstract

Previously, we showed that down-regulation of claudin-10 (CLDN-10) in hepatocellular carcinoma is associated with prolonged disease-free survival after curative surgery. Claudins are important tight junction components. Increasing evidence shows that claudins are involved in cancer progression but each member of claudins is specifically expressed in a variety of malignancies. The biological role of CLDN-10 in hepatocellular carcinoma is unexplored. In the current study, we investigated the CLDN-10 function in two different hepatocellular carcinoma cell lines by in vitro assays with the CLDN-10 overexpression and small interfering RNA-mediated knockdown transfectants. We observed that overexpression of CLDN-10 conferred malignant phenotypes to hepatocellular carcinoma cells, Hep3B, which lack CLDN-10 expression, by promoting cancer cell survival, motility, and invasiveness. More importantly, matrix metalloproteinase 2 (MMP2) was up-regulated. Increase in mRNA transcription and protein expression of membrane type 1-MMP (MT1-MMP) was also observed in the CLDN-10 transfectants, where MT1-MMP was a protease shown to promote intrahepatic metastasis in hepatocellular carcinoma in our earlier study. In addition, CLDN-1, CLDN-2, and CLDN-4 was up-regulated in CLDN-10 overexpression transfectants, indicating that the expression of CLDN-10 in cancer cells might affect the expression levels of its family members. On the contrary, small interfering RNA-based knockdown of CLDN-10 in HLE, an invasive cell line with high level of CLDN-10 expression, abolished invasion and strongly decreased activation of MMPs and claudin members expression. These findings showed that CLDN-10 is functionally involved in hepatocellular carcinoma invasion and is a potential target for hepatocellular carcinoma therapy.

• Authors: Ying Chi Ip, Siu Tim Cheung, Yuk Ting Lee, Jenny C Ho, Sheung Tat Fan
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 11 Pg. 2858-67 (Nov 2007) ISSN: 1535-7163 [Print] United States
• PMID: 18025272 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CLDN1 protein, human
• CLDN2 protein, human
• CLDN4 protein, human
• Claudin-1
• Claudin-4
• Claudins
• Membrane Proteins
• Neoplasm Proteins
• RNA, Small Interfering
• claudin 10
• Matrix Metalloproteinase 2

Topics

• Carcinoma, Hepatocellular (enzymology, pathology)
• Cell Adhesion
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cell Survival
• Claudin-1
• Claudin-4
• Claudins
• Enzyme Activation
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Humans
• Matrix Metalloproteinase 2 (genetics)
• Membrane Proteins (genetics, metabolism)
• Neoplasm Invasiveness
• Neoplasm Proteins (metabolism)
• RNA, Small Interfering
• Up-Regulation