Document Detail


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.
MedLine Citation:
PMID:  19897486     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Chang-Hwan Yoon; Min-Jung Kim; Myung-Jin Park; In-Chul Park; Sang-Gu Hwang; Sungkwan An; Yung-Hyun Choi; Gyesoon Yoon; Su-Jae Lee
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-11-06
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2009-12-28     Completed Date:  2010-01-26     Revised Date:  2011-07-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  226-33     Citation Subset:  IM    
Affiliation:
Department of Chemistry, Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Korea.
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MeSH Terms
Descriptor/Qualifier:
Carcinoma, Hepatocellular / enzymology,  pathology
Cell Line, Tumor
Enzyme Activation
Humans
Liver / enzymology*,  pathology*
Liver Neoplasms / enzymology,  pathology
Membrane Proteins / metabolism*
Neoplasm Invasiveness / pathology*
Protein Kinase C-delta / metabolism*
Proto-Oncogene Proteins c-abl / metabolism*
Signal Transduction*
Chemical
Reg. No./Substance:
0/Membrane Proteins; 0/claudin 1; EC 2.7.10.2/Proto-Oncogene Proteins c-abl; EC 2.7.11.13/Protein Kinase C-delta
Comments/Corrections

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