title: Claudin-1 acts through c-Abl-protein kinase Cdelta (PKCdelta) signaling and has a causal role in the acquisition of invasive capacity in human liver cells.
abstract: Claudins are identified as members of the tetraspanin family of proteins, which are integral to the structure and function of tight junction. Recent studies showed an increase in expression of claudins during tumorigenesis, which is associated with loss of cell-cell contact, dedifferentiation, and invasiveness. However, the molecular basis for the causal relationship between claudin expression and cancer progression is not fully understood yet. In this study, we show that claudin-1 plays a causal role in the acquisition of invasive capacity in human liver cells and that c-Abl-protein kinase Cdelta (PKCdelta) signaling is critical for the malignant progression induced by claudin-1. Overexpression of claudin-1 clearly induced expression of matrix metalloproteinase-2 (MMP-2) and cell invasion and migration in normal liver cells as well as in non-invasive human hepatocellular carcinoma (HCC) cells. Conversely, small interfering RNA targeting of claudin-1 in invasive HCC cells completely inhibited cell invasion. Both c-Abl and PKCdelta are found to be activated in normal liver cell line clones that stably overexpress claudin-1. Inhibition of either c-Abl or PKCdelta alone clearly attenuated MMP-2 activation and impeded cell invasion and migration in both human HCC and normal liver cells expressing claudin-1. These results indicate that claudin-1 is both necessary and sufficient to induce invasive behavior in human liver cells and that activation of c-Abl-PKCdelta signaling pathway is critically required for the claudin-1-induced acquisition of the malignant phenotype. The present observations raise the possibility of exploiting claudin-1 as a potential biomarker for the spread of liver cancer and might provide pivotal points for therapeutic intervention in HCC.
authors.affiliation: Department of Chemistry, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Korea.
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Yoon
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Kim
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.forename: Sungkwan
authors.initials: S
authors.lastname: An
authors.forename: Yung-Hyun
authors.initials: YH
authors.lastname: Choi
authors.forename: Gyesoon
authors.initials: G
authors.lastname: Yoon
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D062445:Claudin-1; D004789:Enzyme Activation; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000473:pathology*; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1; D008565:Membrane Proteins; D016315:Proto-Oncogene Proteins c-abl; D051745:Protein Kinase C-delta