DNA variants of DLC-1, a candidate tumor suppressor gene in human hepatocellular carcinoma.
DNA variants of DLC-1, a candidate tumor suppressor gene in human hepatocellular carcinoma.
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DOI：
10.3892/ijo.23.1.133
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发表时间：
2003-07
影响因子：
5.2
通讯作者：
Sang-won Park;M. Durkin;S. Thorgeirsson;N. Popescu
中科院分区：
文献类型：
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作者：
Sang-won Park;M. Durkin;S. Thorgeirsson;N. Popescu
编码Rho家族小GTP酶调节因子的DLC-1基因在乳腺癌、前列腺癌、结肠癌和肝癌中发生变化，并具有肿瘤抑制基因的几个特征。DLC-1过表达可抑制肝癌细胞的体外生长，完全抑制乳腺肿瘤细胞的体内致瘤性。DLC-1在人肝细胞癌中的失活和异常表达经常与半合子和纯合子基因组缺失和启动子甲基化有关。由于肿瘤细胞中抑癌基因的失活通常也与点突变有关，因此我们用聚合酶链式反应-单链构象多态方法分析了DLC-1基因在17个原发肝癌和18个肝癌细胞系中的突变率。在肝癌细胞系中检测到1个错义突变，位于第12外显子991位密码子(C-->；T转换，Val-->；Ile)。此外，还发现了两种类型的多态：外显子9密码子745处的G-&Gt；T和外显子2下游17个碱基的T--&Gt；C。虽然内含子多态的致病相关性尚不清楚，但DLC-1基因在肝细胞癌中的低突变率表明，基因组缺失和启动子甲基化是导致DLC-1基因表达改变和肿瘤抑制失活的主要原因。
The DLC-1 gene encoding a regulator of the Rho family of small GTPases is altered in breast, prostate, colon, and liver cancer and has several characteristics of a tumor suppressor gene. DLC-1 overexpression causes inhibition of in vitro growth of liver tumor cells and complete suppression of in vivo tumorigenicity of breast tumor cells. Inactivation and aberrant expression of DLC-1 in human hepatocellular carcinoma (HCC) is frequently associated with hemizygous and homozygous genomic deletion and promoter methylation. Since inactivation of tumor suppressor genes in cancer cells is also commonly associated with point mutation, we evaluated the incidence of mutation of the DLC-1 gene by PCR-SSCP in 17 primary HCC and 18 HCC cell lines. One missense mutation was detected at codon 991 of exon 12 (C-->T transition, Val-->Ile) in an HCC cell line. In addition, two types of polymorphisms were identified: a G-->T at codon 745 of exon 9, a T-->C at 17 bp downstream of exon 2. While the pathogenic relevance of the intronic polymorphism is not known, the low rate of mutation of the DLC-1 gene in HCC implies that genomic deletion and promoter methylation primarily account for the altered expression and tumor suppressive inactivation of the DLC-1 gene.