Journal
ONCOGENE
Volume 24, Issue 1, Pages 141-147Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1208244
Keywords
caspase-8; mutation; hepatocellular carcinoma; apoptosis; caspases
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Evidence exists that alterations of the genes encoding apoptosis-related proteins contribute to either development or progression of human cancers. Caspase-8 plays a crucial role in the initiation phase of apoptosis. To explore the possibility that the genetic alteration of caspase-8 gene is involved in the development of hepatocellular carcinomas (HCCs), we have analysed the entire coding region of human caspase-8 gene for the detection of somatic mutations by polymerase chain reaction-single-strand conformation polymorphism in 69 HCCs with low-grade dysplastic nodule (LGDN, n = 2) or high-grade dysplastic nodule (HGDN, n = 2) or without any dysplastic nodules (n = 65). Overall, we detected a total of nine somatic mutations in 69 HCCs (13.0%). Interestingly, all of the nine mutations were an identical frameshift mutation with two base-pair deletion (1225_1226delTG), which would result in a premature termination of amino-acid synthesis in the p10 protease subunit. In a patient sample, we detected the 1225_1226delTG mutation both in HCC and LDGN lesions, suggesting that caspase-8 mutation could be involved in the early stage of HCC carcinogenesis. We expressed the tumor-derived caspase-8 mutant in the cells and found that the mutant abolished cell death activity of caspase-8. Our data indicate that caspase-8 gene is frequently mutated in HCC and the majority of the mutations may be the frameshift mutation 1225_1226delTG. Also, the data suggest that caspase-8 gene mutation might lead to the loss of its cell death function and contribute to the pathogenesis of HCC.
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