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.
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.
Yoon
Chang-Hwan
CH
Department of Chemistry, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Korea.
Kim
Min-Jung
MJ
Park
Myung-Jin
MJ
Park
In-Chul
IC
Hwang
Sang-Gu
SG
An
Sungkwan
S
Choi
Yung-Hyun
YH
Yoon
Gyesoon
G
Lee
Su-Jae
SJ
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
C568108:CLDN1 protein, human; D062445:Claudin-1; D008565:Membrane Proteins; D016315:Proto-Oncogene Proteins c-abl; D051745:Protein Kinase C-delta