CASPASE-8 gene is inactivated by somatic mutations in gastric carcinomas.
Several lines of evidence indicate that deregulation of apoptosis is involved in the mechanisms of cancer development. Caspase-8 activation plays a central role in the initiation phase of apoptosis. The aim of this study was to explore the possibility that genetic alteration of CASPASE-8 gene is involved in the development of human cancers, including gastric cancers. We have analyzed the entire coding region of human CASPASE-8 gene for the detection of somatic mutations in 162 gastric carcinomas (40 early and 122 advanced cancers), 185 non-small cell lung cancers, 93 breast carcinomas, and 88 acute leukemias by PCR-single-strand conformation polymorphism. Of the cancers analyzed, 13 cancers harbored CASPASE-8 somatic mutations. Interestingly, all of the mutations were detected in the advanced gastric cancers (10.7% of the 122 samples). We expressed the tumor-derived caspase-8 mutants in 293T, 293, and HT1080 cells and found that most of the mutants (9 of the 10 mutations tested) markedly decreased the cell death activity of caspase-8. In addition, in the cells with the inactivating caspase-8 mutants, cleavage of poly(ADP-ribose)polymerase was markedly reduced compared with that of wild-type caspase-8. The occurrence of CASPASE-8 mutation and the inactivation of cell death activity by the mutants suggest that CASPASE-8 gene mutation may affect the pathogenesis of gastric cancers, especially at the late stage of gastric carcinogenesis.
Soung
Young Hwa
YH
Department of Pathology, College of Medicine, Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea.
Lee
Jong Woo
JW
Kim
Su Young
SY
Jang
Jin
J
Park
Yong Gyu
YG
Park
Won Sang
WS
Nam
Suk Woo
SW
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; D053181:Caspase 8; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D009154:Mutation; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases