Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The majority of tumors from hereditary nonpolyposis colorectal cancer families and a subset of unselected gastrointestinal and endometrial tumors exhibit a microsatellite mutator phenotype (MMP) that leads to the accumulation of hundreds of thousands of clonal mutations in simple repeat sequences. The mutated genes with positive or negative roles in cell growth or survival in aneuploid gastrointestinal cancer (e.g., APC, K-ras, and p53) are less frequently mutated in near-diploid MMP gastrointestinal tumors. These tumors accumulate mutations in other genes, such as DNA mismatch repair hMSH3 and hMSH6, transforming growth factor-beta type II receptor, and BAX. All these genes carry, within their coding sequences, mononucleotide repeats that are preferred targets for the MMP. Endometrial carcinoma is the most common type of extracolonic neoplasia in the hereditary nonpolyposis colorectal cancer syndrome, but the spectrum of its target cancer genes is not well characterized. Here, we report that endometrial cancer of the MMP also accumulates mutations in genes that are typically mutated in gastrointestinal cancer of the mutator pathway, including BAX (55%), hMSH3 (28%), and hMSH6 (17%). We also report the detection of frameshift mutations in caspase-5, a member of the caspase family of proteases that has an (A)10 repeat within its coding region, in MMP tumors of the endometrium, colon, and stomach (28, 62, and 44%, respectively). We therefore suggest caspase-5 as a new target gene in the microsatellite mutator pathway for cancer.
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PMID:Frameshift mutations at mononucleotide repeats in caspase-5 and other target genes in endometrial and gastrointestinal cancer of the microsatellite mutator phenotype. 1038 66

One of the characteristics of tumors from patients with germline mutations of DNA mismatch repair genes is instability at microsatellite regions (MSI). We analysed alterations at repeated sequences of coding regions, as well as those of 5' upstream regions, in 29 MSI-High colorectal tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) and Turcot syndrome. We found that repeated sequences in 5' upstream regions were altered in these tumors, at considerable frequencies. The (A)10 repeat in the promoter region (position -178 to approximately -169) of the GAPDH gene was altered in 17% of the tumors. The (A)10(TA)9 in the 5' upstream region (position -318 to approximately -291) of the mitochondrial isoleucyl tRNA synthetase gene (IleRS-A), coded in nuclear DNA, was altered in 59% of the tumors, whereas (A)9 in the 5' upstream region (position -859 to approximately -851) of cytoplasmic isoleucyl tRNA synthetase gene (IleRS-B) was not altered. Alteration at repeated sequences in the coding regions were 72% at TGFbetaRII(A)10, 24% at IGFIIR(G)8, 45% at BAX(G)8, 55% at E2F4(CAG)13, 66% at caspase-5 (A)10, 31% at MBD4(A)10, 55% at hMSH3(A)8 and 34% at hMSH6(C)8. The number of altered genes increased with the advancement of carcinoma according to Dukes categories: mean numbers of altered genes within these 10 genes were 2.6 for Dukes A, 4.7 for Dukes B and 7.8 for Dukes C. The mean number for adenomas was 2.0. These results suggest that the MSI phenotype also causes alteration of 5' upstream regions which may affect apoptosis and some mitochondrial functions in HNPCC and Turcot tumors, and that accumulation of altered genes with repeated sequences is associated with the progression of HNPCC and Turcot colorectal tumors.
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PMID:Alterations of repeated sequences in 5' upstream and coding regions in colorectal tumors from patients with hereditary nonpolyposis colorectal cancer and Turcot syndrome. 1152 11

Caspases are cysteine proteases that regulate embryonic development, cell differentiation, tissue homoeostasis, and removal of damaged and harmful cells from the intestine and other parts of the body. Caspase activity is mainly regulated at the posttranslational level, which allows their rapid activation and response to cellular stress and pathogenic stimuli. In most cell types, caspases are initially expressed as inactive proenzymes, which undergo proteolytic cleavage to become functional enzymes. Caspase dysfunction has been associated with intestinal diseases, including inflammatory bowel disease (IBD) and colorectal cancer. Although the roles of caspases have been studied extensively in regulation of apoptosis, recent discoveries have highlighted cell death-independent functions of this protein family. In particular, caspase-1, caspase-4, caspase-5, and caspase-12 are activated during innate immune responses and participate in the formation of the inflammasome. Caspase-8 controls necroptosis of Paneth cells and potentially the death of intestinal epithelial cells in patients with Crohn's disease and appears to be involved in mucosal inflammation. Regulators of caspase-8 might therefore be used to prevent cell death in patients with IBD. Improving our understanding of the regulation and function of caspases in the intestine might lead to new therapeutics for chronic intestinal inflammation and inflammation-associated cancer.
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PMID:Complex roles of caspases in the pathogenesis of inflammatory bowel disease. 2321 99