title: 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.affiliation: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Ying Chi
authors.initials: YC
authors.lastname: Ip
authors.forename: Siu Tim
authors.initials: ST
authors.lastname: Cheung
authors.forename: Yuk Ting
authors.initials: YT
authors.lastname: Lee
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Ho
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D062445:Claudin-1; D062506:Claudin-4; D057167:Claudins; D004789:Enzyme Activation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D034741:RNA, Small Interfering; D015854:Up-Regulation
chemical_list: C568108:CLDN1 protein, human; C491875:CLDN2 protein, human; C568157:CLDN4 protein, human; D062445:Claudin-1; D062506:Claudin-4; D057167:Claudins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C502009:claudin 10; D020778:Matrix Metalloproteinase 2