A novel nonsynonymous variant of matrix metalloproteinase-7 confers risk of liver cirrhosis.
Liver cirrhosis is characterized by progressive accumulation of extracellular matrix following chronic liver injuries. In the extracellular space, the constant turnover of liver matrix is regulated by the matrix metalloproteinase (MMP) class of enzyme. To assess whether genetic variations in MMP would result in diversity of liver cirrhosis, a case-control study of 320 patients with hepatocellular carcinoma, with or without cirrhosis, was conducted. Ten single-nucleotide polymorphism markers from four potential fibrosis-associated genes were selected for genotyping. Among these genes, a nonsynonymous single-nucleotide polymorphism which generates the variation of Gly-137 and Asp-137 in the MMP-7 gene was found to be strongly associated with the development of liver cirrhosis. In contrast to MMP-7(Gly-137) that predominantly secretes out into the cell culture medium, the cirrhosis-associated MMP-7(Asp-137) variant is preferentially localized on the extracellular membranes where it exerts its proteolytic activity on pericellular substrates. Functional analysis demonstrated an increased ability of the MMP-7(Asp-137) variant to associate with the cell surface CD151 molecule. In wound-healing and Boyden chamber assays, cell motility was specifically enhanced with the expression of MMP-7(Asp-137) as compared to the cells expressing MMP-7(Gly-137). These results demonstrate that the MMP-7(Asp-137) variant confers a gain-of-function phenotype for MMP-7.


CONCLUSIONS
We have identified a novel genetic association of MMP-7(Asp-137) variant with liver cirrhosis in patients with hepatocellular carcinoma. Whether the MMP-7 variant can be a new marker for liver cirrhosis will be further studied.
Hung
Tzu-Min
TM
Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan.
Chang
Shin C
SC
Yu
Wei-Hsuan
WH
Wang
Yu-Wen
YW
Huang
Cheng
C
Lu
Shao-Chun
SC
Lee
Po-Huang
PH
Chang
Ming-Fu
MF
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D060185:Tetraspanin 24
D015703:Antigens, CD; D015415:Biomarkers; C554715:CD151 protein, human; D060185:Tetraspanin 24; D020783:Matrix Metalloproteinase 7