Caspase-8 gene is frequently inactivated by the frameshift somatic mutation 1225_1226delTG in hepatocellular carcinomas.
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.
Soung
Young Hwa
YH
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
Lee
Jong Woo
JW
Kim
Su Young
SY
Sung
Yong Jik
YJ
Park
Won Sang
WS
Nam
Suk Woo
SW
Kim
Sang Ho
SH
Lee
Jung Young
JY
Yoo
Nam Jin
NJ
Lee
Sug Hyung
SH
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000483:Alleles; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D053181:Caspase 8; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D016368:Frameshift Mutation; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D011485:Protein Binding
D048868:Adaptor Proteins, Signal Transducing; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases