A Novel Nonsynonymous Variant of Matrix Metalloproteinase-7 Confers Risk of Liver Cirrhosis
A Novel Nonsynonymous Variant of Matrix Metalloproteinase-7 Confers Risk of Liver Cirrhosis
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DOI：
10.1002/hep.23137
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发表时间：
2009-10-01
期刊：
影响因子：
13.5
通讯作者：
Chang, Ming-Fu
中科院分区：
文献类型：
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作者：
Hung, Tzu-Min;Chang, Shin C.;Chang, Ming-Fu
肝硬化的特征是在慢性肝损伤后细胞外基质进行性积聚。在细胞外间隙，肝脏基质的持续更新受基质金属蛋白酶（MMP）这类酶的调节。为了评估MMP的基因变异是否会导致肝硬化的多样性，对320例肝细胞癌患者（伴或不伴肝硬化）进行了一项病例对照研究。从四个潜在的与纤维化相关的基因中选取了十个单核苷酸多态性标记进行基因分型。在这些基因中，发现MMP - 7基因中一个产生甘氨酸 - 137和天冬氨酸 - 137变异的非同义单核苷酸多态性与肝硬化的发展密切相关。与主要分泌到细胞培养基中的MMP - 7（甘氨酸 - 137）不同，与肝硬化相关的MMP - 7（天冬氨酸 - 137）变体优先定位在细胞外膜上，在那里它对细胞周围的底物发挥其蛋白水解活性。功能分析表明，MMP - 7（天冬氨酸 - 137）变体与细胞表面CD151分子结合的能力增强。在伤口愈合和博伊登小室试验中，与表达MMP - 7（甘氨酸 - 137）的细胞相比，表达MMP - 7（天冬氨酸 - 137）的细胞运动性显著增强。这些结果表明，MMP - 7（天冬氨酸 - 137）变体赋予了MMP - 7一种功能获得性表型。结论：我们已经确定了MMP - 7（天冬氨酸 - 137）变体与肝细胞癌患者肝硬化的一种新的遗传关联。MMP - 7变体是否可作为肝硬化的一个新标记将进一步研究。（《肝脏病学》2009年；50卷：1184 - 1193页）
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 NMP-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. Conclusion: 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. (HEPATOLOGY 2009;50:1184-1193.)