Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of the ras oncogene in aberrant crypt foci was studied by both in situ hybridization and immunohistochemical approaches. Aberrant crypt foci are hypothesized to represent the earliest identifiable microscopic lesions of colon cancer in rodent colons. Sprague-Dawley male rats were injected with azoxymethane (20 mg/kg s.c.) once. Twelve weeks later, aberrant crypt foci were identified topographically, microdissected and processed for histology. In situ hybridization with an antisense oligomer of c-ras demonstrated increased expression of ras-specific RNA in aberrant crypts compared to normal crypts. A low amount of non-specific hybridization was obtained with the corresponding sense oligomer. The percentage of cells with grains (labeling index) was calculated in early and advanced aberrant crypt foci. This index was also calculated in normal appearing crypts. The labeling indices for the early and advanced aberrant crypt foci were significantly greater than that of normal crypts (18.0 and 25.0 versus 11.9). In the same tissue specimens, immunohistochemical staining for ras p21 with the monoclonal antibody (Y13-259) revealed strong staining intensity in early aberrant crypts (15/22) and advanced aberrant crypts (22/30) compared to normal crypts (3/50). The immunohistochemical results demonstrate the presence of elevated levels of ras p21 in the same tissue as increased levels of ras-specific message. This investigation provides the earliest demonstration of increased expression of the ras oncogene in precursor lesions of colon cancer possessing dysplastic features.
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PMID:Expression of ras oncogene mRNA and protein in aberrant crypt foci. 142 46

To gain a better understanding of the biologic development of rectal adenocarcinomas, the authors evaluated the level of ras gene protein product (p21) in the available material of 74 Dukes' B adenocarcinomas, 64 Dukes' C adenocarcinomas, and 60 lymph-node metastases resected at the University of Chicago Medical Center between 1965 and 1981. Pathologic slides and archival paraffin blocks were retrieved for confirmation of the original diagnosis and measurement of p21 content. P21 titers were obtained using the RAP-5 monoclonal antibody in a semiquantitative immunohistochemical assay. Titer was expressed as the highest dilution giving definitive staining using the avidin-biotin peroxidase method. The analysis indicated that a higher percentage of Dukes' stage C rectal adenocarcinomas had high (greater than or equal to 1:40,000) p21 titers than Dukes' B adenocarcinomas (68.8 vs. 51.4 percent, respectively, P less than 0.05). In view of recent data suggesting that ras oncogene expression confers invasive and metastatic capabilities to NIH 3T3 cells, the authors believe this study offers evidence that overexpression of ras oncogene with overproduction of p21 protein product may be an important prerequisite for the acquisition of metastatic capabilities in the early stages of colon cancer.
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PMID:Ras oncogene and the acquisition of metastasizing properties by rectal adenocarcinoma. 266 52

In the present study we used monoclonal antibodies to investigate the expression of phosphotyrosine, c-myc and c-Ha-ras proteins along the crypt continuum of normal and transformed rat colon tissue. Colon cancer was induced by administration of dimethylhydrazine. Particular attention was focused on the immunohistochemical pattern of murine colon mucosa during preneoplastic stages so as to permit the identification of putative changes in the expression/location of the oncoproteins prior to frank neoplasia. The immunohistochemical analysis of tyrosinephosphorylated proteins in the normal rat indicated that positive staining was mostly restricted to the lower colonic crypt zones. The carcinogenetic insult altered the magnitude and positional profile of phosphotyrosine along the colon crypt axis during the preneoplastic period. An intense positive reaction was observed in the upper crypt regions. Four weeks following the last DHM administration, viz. before tumor appearance, positive staining was evident in invasive adenocarcinoma tissue. In contrast to phosphotyrosine, the feeble c-myc immunohistochemical staining of normal rat colonic did not exhibit a focal topology. However, following DMH administration and prior to frank neoplasia, a substantial increase in the staining intensity for c-myc was noted, confined mostly to the supranuclear region of luminal cells. Invasive adenocarcinomas displayed intense cytoplasmic c-myc immunoreactivity. p21 c-Ha-ras expression and location along the colon crypt axis showed a different pattern when compared to p62 c-myc and phosphotyrosine. The p21 c-Ha-ras protein was prominently expressed in surface epithelium of normal and DMH-treated rats. Midcrypt colonocytes exhibited moderate p21 ras staining; in contrast, proliferating colonic cells resident in the lower crypt regions were consistently negative. These results suggest that c-Ha-ras gene product plays an important contributory role in determining the differentiated phenotype of the colonic cell.
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PMID:Phosphotyrosine, p62 c-myc and p21 c-Ha-ras proteins in colonic epithelium of normal and dimethylhydrazine-treated rats: an immunohistochemical analysis. 753 85

Mutated p21 ras proteins contain single substituted amino acid residues and represent cancer-specific proteins. The current study examined whether primed T cell immunity to mutant p21 ras proteins and/or peptides can be detected in patients with pancreatic or colon cancer. Studies focused on the aspartic acid substitution in amino acid position 12 (denoted D12) as the commonest mutation in gastrointestinal malignancy. Peripheral blood lymphocytes from patients or normal individuals were tested for the ability to proliferate in response to normal or mutated ras peptides or proteins. T-cell responses were defined as a stimulation index of > 2.0. Results showed that 7 of 16 (44%) pancreatic cancer patients responded to ras-D12 peptide. Responses to ras-D12 protein were studied in only the last four patients that responded to D12 peptides. Three of the 4 patients that responded to ras-D12 peptide showed a substantial response to p21 ras-D12 protein (stimulation indices of 12, 8, and 24). Specificity was validated by examining responses to normal and alternate ras peptides and proteins. T-cell responses to ras-D12 peptides were detected in only 2 of 25 (8%) colon cancer patients. None of 11 normal individuals tested had positive responses to normal or mutant ras p21 proteins and/or peptides. Thus, CD4+ T-cell immunity to the mutated segment of ras protein is present in some patients with gastrointestinal cancer.
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PMID:CD4+ T-cell immunity to mutated ras protein in pancreatic and colon cancer patients. 760 15

Transforming growth factor-beta (TGF-beta) inhibits cell cycle progression of many types of human cells by arresting them in the G1 phase of the cell cycle. The arrest is mediated through interactions of various cyclin-dependent protein kinases (CDKs) and their inhibitors. We demonstrate that treatment with TGF-beta induces increased levels of WAF1/Cip1/p21, a potent inhibitor of various cyclin-CDK kinase activities, in two colon cancer cell lines (LS1034 and LS513), which are sensitive to TGF-beta-induced growth arrest. The induction in at least one of these cell lines (LS1034,p53-) is p53-independent. No WAF1 induction was observed after TGF-beta treatment in a third cell line (HT-29), which is completely insensitive to the cytoinhibitory effect of TGF-beta. In both LS513 and LS1034, WAF1 induction correlated with reduced cyclin E-associated kinase activity in vitro and suppression of the retinoblastoma susceptibility gene (Rb) protein phosphorylation in vivo. In addition, WAF1 was physically associated with cyclin E in the two sensitive cell lines. These results suggest that WAF1/Cip1/p21 is a mediator of cellular sensitivity to TGF-beta.
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PMID:Potential role of WAF1/Cip1/p21 as a mediator of TGF-beta cytoinhibitory effect. 789 Jun 1

In our previous study, we demonstrated that azoxymethane (AOM) treatment significantly enhanced the expression of ras p21, the protein product of ras genes, and that the dietary administration of chemopreventive agents such as D,L-alpha-difluoromethylornithine (DFMO), a irreversible inhibitor of ornithine decarboxylase, and piroxicam, a non-steroidal anti-inflammatory drug (NSAID), exerted a significant inhibitory effect on AOM-induced ras p21 expression. In the present study, which is an extension of our earlier investigation, we have determined the effect of DFMO and piroxicam on mutational activation of ras protooncogenes during AOM-induced colon carcinogenesis. Groups of male F344 rats were fed the modified AIN-76A diet containing 0 or 150 p.p.m. piroxicam, or 4000 p.p.m. DFMO and administered s.c. AOM dissolved in normal saline at a dose rate of 15 mg/kg body wt, once weekly, for 4 weeks. Vehicle control groups received s.c. equal volumes of normal saline. Groups of animals were then killed at 0, 4, 16, 24 or 32 weeks after last AOM or saline injection. AOM-induced colon tumors and colonic mucosa from AOM treated as well as saline treated animals were analyzed for point mutations in K- and H-ras protooncogenes by a combination of polymerase chain reaction mediated restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. Our results demonstrate that of the total 65 AOM-induced colon tumors analyzed, 45/50 (90%) obtained from AOM-treated animals fed the control diet, 4/11 (36%) from AOM-treated animals fed piroxicam diet, and 1/4 (25%) from AOM-treated animals fed the DFMO diet, contained single-point mutations occurring specifically at the second nucleotide of codon 12 which were identified exclusively as G to A transitions in case of K-ras, and G to A transitions and also G to T transversions in H-ras. Similar point mutations were identified in colonic mucosa of 21/30 (70%) of AOM-treated animals fed the control diet, 10/30 (33%) of AOM-treated animals fed piroxicam diet, and none of 30 (0%) of AOM-treated animals fed DFMO diet. These results indicate that the administration of piroxicam and DFMO may inhibit the selective amplification of AOM-induced initiated cells carrying mutated ras genes. Dietary DFMO exerted more pronounced inhibition of selective amplification of initiated cells containing AOM-induced mutant ras. Data suggest that determination of ras activation may be a useful marker for chemoprevention of colon cancer.
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PMID:Modulation of azoxymethane-induced mutational activation of ras protooncogenes by chemopreventive agents in colon carcinogenesis. 803 6

p53 induction and cell cycle arrest occur following DNA damage, possibly to allow repair prior to replication. p21WAF1/CIP1, a cyclin-cyclin-dependent kinase inhibitor and proliferating cell nuclear antigen-interacting protein, is induced by p53 and mediates the cell cycle arrest. To investigate a role for p21 in DNA repair in vivo, we studied the expression of in vitro damaged reporter DNA transfected into p21 +/+ or -/- HCT116 human colon cancer cells. Introduction of UV-damaged or cisplatinum-damaged cytomegalovirus-driven beta-galactosidase reporter DNA into tumor cells revealed a significant decrease (2-5-fold) in reporter expression in p21 -/- versus +/+ cells. In the absence of DNA damage, there was a significant increase (2-3-fold) in the number of 6-TG-resistant colonies derived from p21 -/- versus +/+ cells. Reintroduction of wild-type p21, but not a p21 C-terminal truncation mutant which lacks the proliferating cell nuclear antigen interaction domain, stimulated (2-3-fold) the repair capacity of the p21-deficient cells. We conclude that p21 deficiency is associated with a defect in DNA repair, which could lead to an increased sensitivity of tumor cells to DNA damage.
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PMID:Repair Defect in p21 WAF1/CIP1 -/- human cancer cells. 862 93

The myc gene family has been implicated in multiple cell processes including proliferation, differentiation, tumorigenesis, and apoptosis. For its cellular growth promoting function, Myc must heterodimerize with Max. To study the effect of Myc inactivation on the growth and differentiation properties of epithelial tumor cells, we transfected the H-630 human colon cancer cell line with bm-max, a mutant Max protein in which DNA-binding activity has been abolished. Cells expressing high levels of bm-Max grow poorly, and the morphology of both colonies and single cells is altered. Moreover, increased bm-Max expression results in a prolonged G alpha/G1 phase accompanied by induced expression of p21 (WAF1/CIP1), elevated levels of alkaline phosphatase (ALP) activity, and accumulation of large fat granuli within the cells. These distinctive cell characteristics are associated with differentiation processes in numerous malignant cell lines. The results of this study support a model in which sequestering of endogenous Myc and Max proteins into "basic mutant" dimers lacking DNA-binding activity is sufficient both to inhibit proliferation and to induce changes in cell behavior consistent with differentiation.
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PMID:c-Myc inactivation by mutant Max alters growth and morphology of NCI-H-630 colon cancer cells. 884 36

Alterations of the N-linked carbohydrate core structure of cell surface glycoproteins (beta 1-6 branching) can be detected by phytohemagglutinin (PHA-L) lectin binding and has been linked to tumor progression and K-ras activation in colon cancer. The purpose of this study was to determine the prevalence of this carbohydrate alteration and its relationship to K-ras activation in pancreatic cancer. Nine human pancreatic cancer cell lines and 4 colon lines as controls were grown under standard tissue culture conditions. K-ras genome analysis was performed by polymerase chain reaction amplification and sequencing. The proportion of cellular p21-ras bound to GTP (ras-GTP level) was determined using immunoprecipitation of 32P-labeled cell lysates followed by thin layer chromatography and phosphoimaging analysis. Lectin blot analysis was performed on crude membrane preparations. Sensitivity to lectins was assessed with cell culture thymidine incorporation. Of 9 pancreatic cancer lines tested, 3 had wild type K-ras, 2 had heterozygous and 4 had homozygous mutations in codon 12 of K-ras. These genotypes correlated strongly with the level of ras-GTP measured. K-ras mutants had increased levels of ras-GTP compared to wild-type cell lines. PHA-L binding to cell membranes correlated positively with ras-GTP levels in 7 out of 9 cell lines. PHA-L toxicity was greatest in cells with positive PHA-L reactivity on Western blotting. A positive correlation between the presence of K-ras mutation, increased ras-GTP level, and increased cell surface beta 1-6 N-linked carbohydrate exists in pancreatic cancer cell lines.
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PMID:Phytohemagglutinin-L (PHA-L) lectin surface binding of N-linked beta 1-6 carbohydrate and its relationship to activated mutant ras in human pancreatic cancer cell lines. 894 26

Although epidemiological and experimental studies have indicated a strong relationship between types and amount of dietary fat and colon tumorigenesis, the modulating effects of these nutritional factors at the molecular level have not been fully elucidated. Transforming proteins encoded by activated ras genes have been implicated in the etiology of many human malignancies, including colon cancer. It is now well established that the transforming ability of ras-p21 critically depends on its correct localization in plasma membrane. The posttranslational processing of the cytosolic precursor (pro-ras), as it is synthesized in the cytoplasm, and its proper anchorage to the cytoplasmic face of plasma membrane are determined by an important intermediate metabolite of dietary fat and an enzyme system that includes farnesyl protein transferase. To provide an understanding of the molecular basis of the relationship between the types and amount of dietary fat and the transforming function of ras, especially during the stages of promotion and progression of colon tumor development, we investigated the effect of various types and amount of dietary fat on the expression of ras-p21 during azoxymethane (AOM)-induced colon carcinogenesis. Male F344 rats were fed the semipurified American Institute of Nutrition-76A diet containing low-fat corn oil and were given s.c. injections of AOM dissolved in normal saline at a dose rate of 15 mg/kg body weight, once weekly, for 2 weeks. Control animals received s.c. injections of equal volumes of normal saline. Beginning 1 day after the second AOM or saline injection, groups of animals intended for the treatment with different types of high-fat dietary regimens were fed the semipurified American Institute of Nutrition-76A diets containing high levels of high-fat corn oil (HFCO) rich in omega-6 fatty acids or high levels of high-fat fish oil (HFFO) rich in omega-3 fatty acids; the remaining animals in experimental and control groups were continued on the low-fat corn oil diet until termination of the experiment. Groups of animals were sacrificed 1, 12, or 36 weeks after the last AOM or saline injection, and their colonic mucosa and grossly visible colon tumors from rats sacrificed 36 weeks after the last AOM injection were analyzed for the levels of expression of ras-p21. We found that AOM induced increasingly higher levels of ras-p21 expression with advancing stages of colon tumor development. The HFCO diet resulted in enhanced expression of AOM-induced ras-p21 as observed 36 weeks after the last AOM injection. In contrast, feeding the HFFO diet inhibited AOM-induced ras-p21 expression. These results correlate with increased incidence and multiplicity of grossly visible colon tumors in AOM-treated animals fed a HFCO diet versus decreased incidence and lower multiplicity of colon tumors in their counterparts on the HFFO diet. Further analysis of ras-p21 levels in cytosol and plasma membrane revealed that feeding a HFFO diet resulted in increasing accumulation of ras-p21 in cytoplasm with a concomitant decrease in membrane-bound ras-p21 levels as observed in animals sacrificed 12 and 36 weeks after the last AOM injection. Thus, the dietary HFCO may promote colon tumorigenesis by increasing ras-p21 expression, whereas HFFO appears to exert its antitumor activity by interfering with posttranslational modification and membrane localization of ras-p21.
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PMID:Dietary fat and colon cancer: modulating effect of types and amount of dietary fat on ras-p21 function during promotion and progression stages of colon cancer. 900 May 64


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