On the coverInactivating mutations of caspase-8 gene in colorectal carcinomas☆
Section snippets
Tissue samples, microdissection, and plasmids
Paraffin-embedded histological sections of 82 colorectal adenomas (40 low-grade dysplasias and 42 high-grade dysplasias) and 98 invasive colorectal carcinomas were obtained from the Catholic University of Korea-affiliated hospitals (Seoul, Korea). The term invasive carcinoma means, strictly, a cancer that has invaded beyond the muscularis mucosa. The carcinomas originated from cecum (n = 2), ascending colon (n = 18), transverse colon (n = 6), descending colon (n = 3), sigmoid colon (n = 27),
Mutations and allelic status of the caspase-8 gene
Through the microdissection technique, we selectively procured tumor cells and normal cells from histological sections of 180 colon tumors. Genomic DNA was isolated and analyzed for the potential mutations in the coding region of the caspase-8 gene by PCR-SSCP analysis. Enrichment and direct DNA sequence analysis of aberrantly migrating bands led to the identification of 5 mutations in 98 invasive carcinomas (5.1%) (Table 1; Figure 1) but none in 82 adenomas (0%). None of the corresponding
Discussion
The aim of this study was to address whether human colon carcinoma has caspase-8 gene mutation. If so, the next aim was to address whether these mutations inactivated the proapoptotic activity of caspase-8. We found that in colon carcinoma, but not in colon adenoma, the caspase-8 gene is somatically mutated. Moreover, the functional study showed that the cancer-derived caspase-8 mutants showed losses of apoptotic function. These data, together with the earlier reports on the inactivating
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Supported by funding from the Molecular Medicine Research Group program from the Ministry of Science and Technology of Korea (Grant M10106000075-02B1700-01810) and by funds from POSCO (Grant 20027045).