CASPASE-8 gene is inactivated by somatic mutations in gastric carcinomas.

Abstract

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.

• Authors: Young Hwa Soung, Jong Woo Lee, Su Young Kim, Jin Jang, Yong Gyu Park, Won Sang Park, Suk Woo Nam, Jung Young Lee, Nam Jin Yoo, Sug Hyung Lee
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 3 Pg. 815-21 (Feb 01 2005) ISSN: 0008-5472 [Print] United States
• PMID: 15705878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• FADD protein, human
• Fas-Associated Death Domain Protein
• CASP8 protein, human
• Caspase 8
• Caspases

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Alleles
• Apoptosis (genetics)
• Caspase 8
• Caspases (genetics, metabolism)
• Fas-Associated Death Domain Protein
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Humans
• Mutation
• Stomach Neoplasms (enzymology, genetics, pathology)