Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Male Wistar rats were fed a choline-deficient, L-amino acid-defined (CDAA) diet alone or in combination with a nitrone-based free radical trapping agent, phenyl N-tert-butyl nitrone (PBN) in the drinking water at the concentrations of 0.013, 0.065, and 0.130% for 12 weeks. PBN inhibited the changes that are normally induced in the livers of rats by the CDAA diet feeding, i.e., development of putative preneoplastic lesions, proliferation of connective tissue, reduction of glutathione S-transferase activity, formation of 8-hydroxyguanine in DNA, and an increase in inducible cyclo-oxygenase (COX2) activity. PBN, however, did not prevent the increases in the COX2 mRNA or protein levels brought on by the CDAA diet These results indicate that the loss of glutathione S-transferase activity and COX2 induction may play significant roles in rat liver carcinogenesis by the CDAA diet and that PBN prevents neoplasia not only by its radical scavenging activity but also by inhibiting COX2 activity at the catalytic level.
 ...
PMID:Inhibition by phenyl N-tert-butyl nitrone of early phase carcinogenesis in the livers of rats fed a choline-deficient, L-amino acid-defined diet. 978 98

Colorectal carcinoma remains the second most common malignancy in the western world. Mortality has remained stable despite advances in surgical and adjuvant radio- and chemotherapy regimens. This has renewed interest in the understanding of the basic principles of the molecular biology of colorectal carcinogenesis. The condition is characterised by multiple mutations in common oncogenes and tumour suppressor genes encompassing the inherited conditions familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. The latter is characterised by genomic instability due to mismatch repair gene defects. These conditions and the role of the tumour protease systems, e.g. the plasminogen activation system and the matrix metalloproteinases, involved in the degradation of the extracellular matrix, provide an ideal role model for the study of carcinogenesis. The understanding and future application of these basic mechanisms, combined with the recent innovative work on the potential prophylactic role of COX2 inhibition, may provide further insight in the ultimate quest for a 'cure'. In the long-term, this concept may have to be achieved at the molecular level.
 ...
PMID:The molecular biology of colorectal cancer development and the associated genetic events. 1064 73

Studies have indicated that inflammation, in conjunction with the production of reactive oxygen species, may play a key role in lung cancer development. In this study, 250 lung cancer patients and 214 controls were genotyped for polymorphisms of the inflammation-related genes prostaglandin synthase-2/cyclooxygenase-2 (COX2/PTGS2), interleukin-6 (IL6), interleukin-8 (IL8) and peroxisome proliferator-activated receptor gamma (PPARg). We found that carriers of the C allele of a polymorphism in the 3'-UTR of COX2 had a significantly increased risk of lung cancer, with odds ratios of 4.28 (95% CI, 2.44-7.49) for homozygotes and 2.12 (95% CI, 1.25-3.59) for heterozygotes. Additionally, we found that an IL8 promoter polymorphism had a protective effect for lung cancer in female subjects, whereas an IL6 promoter polymorphism was only associated with risk of squamous cell carcinoma. This is the first study implicating polymorphisms in inflammatory genes in the risk of lung cancer.
Carcinogenesis 2004 Feb
PMID:Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. 1460 94

Subtraction hybridization was earlier used to obtain cDNA clones corresponding to human genes upregulated in HIV-associated centroblast lymphoma (CL) as compared with HIV-associated immunoblast lymphoma (IL). With inverse subtraction hybridization, clones were isolated that correspond to genes upregulated in IL compared with CL. In addition to cDNAs characterized earlier, the resulting clones contained several (seven CL-specific and three IL-specific) sequences with unknown functions. To identify the lymphoma-specific genes that are overexpressed in early carcinogenesis, Northern blotting was used to assess the level of gene transcription in two human fibroblast lines and in their derivatives immortalized with either a temperature-sensitive mutant of SV-40 or with pSV3neo carrying the SV-40 A gene, considering the latter as a model of early cell malignant transformation. Increased expression in at least one immortalized line compared with normal fibroblasts was observed for set, a-myb, ND1, ND2, ND4 (NADH dehydrogenase subunits 1, 2, and 4), COX2, COX3 (cytochrome-c-oxidase subunits 2 and 3), KIAA0129, and the gene corresponding to cDNA hss2-1-7-10. High expression of these genes was assumed to be associated not only with lymphomogenesis, but also with early transformation (immortalization) of other, nonlymphoid cells. Expression of the calpain gene and the gene corresponding to cDNA hss2-2-9-5 proved to be lower in immortalized than in normal fibroblasts. This was considered indicative of an alternative mechanism of fibroblast transformation or of different processes regulating the expression of these genes in early and late carcinogenesis.
 ...
PMID:[Analysis of expression of a series of lymphoma-specific genes in human fibroblasts immortalized by SV40 virus]. 1512 32

In the human colon, arachidonic acid is metabolized primarily by cyclooxygenase (COX) and arachidonate lipoxygenase (ALOX) to bioactive lipids, which are implicated in colon cancer risk. Several polymorphisms in ALOX and COX genes have been identified, including G-1752A, G-1699A and Glu254Lys in ALOX5; Gln261Arg in ALOX12; Leu237Met and Val481Ile in COX1; and C-645T and Val511Ala in COX2. Because of the significant role of arachidonic acid metabolism in colon cancer, we hypothesized that these polymorphisms could influence susceptibility to colon cancer. We addressed this hypothesis in African-Americans and Caucasians using colon cancer cases (n = 293) and hospital- (n = 229) and population-based (n = 304) control groups. Polymorphisms did not differ between the control groups (P > 0.05); thus, they are combined for all analyses presented. ALOX5 Glu254Lys and COX2 C-645T and Val511Ala allele frequencies differed between Caucasians and African-American controls (P < 0.001). The ALOX5 -1752 and -1699 polymorphisms were in linkage disequilibrium (P < 0.001) and associated with a decreased risk in Caucasians in ALOX5 haplotype analyses (P = 0.03). Furthermore, an inverse association was observed between A alleles at positions -1752 and -1699 of ALOX5 and colon cancer risk in Caucasians, but not in African-Americans. Caucasians with A alleles at ALOX5 -1752 had a reduced odds of colon cancer versus those with G alleles [odds ratio (OR) (GA versus GG), 0.63; 95% confidence interval (CI), 0.39-1.01; OR (AA versus GG), 0.33; 95% CI, 0.07-1.65, P(trend) = 0.02]. Similar results were observed for ALOX5 G-1699A [OR (GA versus GG), 0.59, 95% CI, 0.37-0.94; OR (AA versus GG), 0.27, 95% CI, 0.06-1.32, P(trend) = 0.01]. Statistically significant associations with colon cancer were not observed for the other polymorphisms investigated. We have shown for the first time that a haplotype containing ALOX5 G-1752A and G-1699A in a negative regulatory region of the promoter may influence colon cancer risk in Caucasians.
Carcinogenesis 2004 Dec
PMID:Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk. 1530 83

In many cases, silencing of gene expression by CpG methylation is causally involved in carcinogenesis. Furthermore, cancer-specific CpG methylation may serve as a tumor marker. In order to identify candidate genes for inactivation by CpG methylation in prostate cancer, the prostate cancer cell lines LNCaP, PC3, and Du-145 were treated with 5-aza-2' deoxycytidine and trichostatin A, which leads to reversion of epigenetic silencing. By microarray analysis of 18,400 individual transcripts, several hundred genes were found to be induced when compared with cells treated with trichostatin A. Fifty re-expressed genes were selected for further analysis based on their known function, which implied a possible involvement in tumor suppression. Twelve of these genes showed a significant degree of CpG methylation in their promoters. Six genes were silenced by CpG methylation in the majority of five analyzed prostate cancer cell lines, although they displayed robust mRNA expression in normal prostate epithelial cells obtained from four different donors. In primary prostate cancer samples derived from 41 patients, the frequencies of CpG methylation detected in the promoter regions of these genes were: GPX3, 93%; SFRP1, 83%; COX2, 78%; DKK3, 68%; GSTM1, 58%; and KIP2/p57, 56%. Ectopic expression of SFRP1 or DKK3 resulted in decreased proliferation. The expression of DKK3 was accompanied by attenuation of the mitogen-activated protein kinase pathway. The high frequency of CpG methylation detected in the promoters of the identified genes suggests a potential causal involvement in prostate cancer and may prove useful for diagnostic purposes.
 ...
PMID:Functional epigenomics identifies genes frequently silenced in prostate cancer. 1589 13

Use of non-steroid anti-inflammatory drugs (NSAIDs) has been associated with decreased risk of breast cancer in epidemiological studies. Thus, a high-inflammatory response may be associated with increased breast cancer risk. It is thus possible that genetic variations leading to a modified inflammatory response will influence breast cancer risk. The purpose of this study was to determine if polymorphisms associated with an altered inflammatory response are associated with breast cancer risk, and to investigate the possible interaction with lifestyle factors such as alcohol use, smoking and NSAID use. We matched 361 female breast cancer cases with 361 controls, nested within the prospective 'Diet, Cancer and Health' study. Carriers of the variant Ala-allele of PPARgamma2 Pro12Ala were at lower risk of breast cancer (IRR=0.67, 95% CI=0.46-0.97). This was primarily due to an interaction with alcohol consumption. Alcohol consumption was associated with a 1.21-fold increased risk of breast cancer per 10 g alcohol/day (95% CI=1.06-1.35) among homozygous wild-type carriers, whereas alcohol was not associated with breast cancer risk among variant allele carriers (P for interaction=0.005). Non-users of NSAID, who were carriers of the variant allele of PPARgamma2 Pro12Ala, were at lower risk of breast cancer (IRR=0.44; 95% CI=0.26-0.73) compared with non-users carrying wild-type alleles (P for interaction=0.03). No effects were found for IL6 G-174C, IL8 T-251A and COX2 T8473C. Our results suggest that PPARgamma2 Pro12Ala is an important determinant in alcohol mediated breast carcinogenesis. We also observe interaction between NSAID, alcohol consumption and PPARgamma2 Pro12Ala genotype in relation to breast cancer risk.
Carcinogenesis 2007 Feb
PMID:Peroxisome proliferator-activated [corrected] receptor-gamma2 [corrected] Pro12Ala, interaction with alcohol intake and NSAID use, in relation to risk of breast cancer in a prospective study of Danes. 1695 87

The up-regulation of the inducible form of cyclooxygenase (COX-2), a central enzyme in the prostaglandin (PG) biosynthetic pathway, occurs in many epithelial tumors and has been associated with tumor cell proliferation and angiogenesis. To better understand the role of COX-2 in skin tumor development, we generated transgenic mice that overexpress COX-2 under the control of the keratin 14 promoter. We previously reported (Cancer Res. 62: 2516, 2002) that these mice, referred to as keratin 14 (K14).COX2 mice, were unexpectedly very resistant to 12-O-tetradecanoylphorbol 13-acetate (TPA) tumor promotion. The current studies were undertaken to determine the mechanism of this resistance and determine if it was restricted to TPA promotion. Transgenic and wild-type mice were subjected to a complete carcinogenesis protocol using 7,12-dimethylbenz[a]anthracene (DMBA) only, as well as a two-stage protocol using DMBA plus an unrelated tumor promoter, anthralin. In addition, the responses of transgenic and wild-type mice to TPA in terms of induction of proliferation and various down-stream mediators were examined. The TPA resistance phenotype correlated with a reduced ability to induce ornithine decarboxylase, interleukin-1alpha, and tumor necrosis factor-alpha and a reduced proliferation response. This resistance phenotype appears to be restricted to phorbol ester promotion because K14.COX2 mice developed six times more tumors than wild-type mice when anthralin was used as the tumor promoter. Additionally, K14.COX2 mice treated only with DMBA developed approximately 3.5 times more tumors than wild-type mice, suggesting that PGs have intrinsic tumor promoting activity. We conclude that the role of PGs in skin tumorigenesis is context dependent.
 ...
PMID:The effect of cyclooxygenase-2 overexpression on skin carcinogenesis is context dependent. 1758 68

Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that aberrant induction of COX-2 and up-regulation of the prostaglandin cascade play a significant role in carcinogenesis, and reciprocally, blockade of the process has strong potential for cancer prevention and therapy. Supporting evidence includes the following: [1] expression of constitutive COX-2-catalyzed prostaglandin biosynthesis is induced by most cancer-causing agents including tobacco smoke and its components (polycylic aromatic amines, heterocyclic amines, nitrosamines), essential polyunsaturated fatty acids (unconjugated linoleic acid), mitogens, growth factors, proinflammatory cytokines, microbial agents, tumor promoters, and other epigenetic factors, [2] COX-2 expression is a characteristic feature of all premalignant neoplasms, [3] COX-2 expression is a characteristic feature of all malignant neoplasms, and expression intensifies with stage at detection and cancer progression and metastasis, [4] all essential features of carcinogenesis (mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis, and immunosuppression) are linked to COX-2-driven prostaglandin (PGE-2) biosynthesis, [5] animal studies show that COX-2 up-regulation (in the absence of genetic mutations) is sufficient to stimulate the transformation of normal cells to invasive cancer and metastatic disease, [6] non-selective COX-2 inhibitors, such as aspirin and ibuprofen, reduce the risk of human cancer and precancerous lesions, and [7] selective COX-2 inhibitors, such as celecoxib, reduce the risk of human cancer and precancerous lesions at all anatomic sites thus far investigated. Results confirming that COX-2 blockade is effective for both cancer prevention and therapy have been tempered by observations that some COX2 inhibitors pose a risk to the cardiovascular system, and more studies are needed in order to determine if certain of these drugs can be taken at dosages that prevent cancer without increasing cardiovascular risk. It is emphasized that the "inflammogenesis model of cancer" is not mutually exclusive and may in fact be synergistic with the accumulation of somatic mutations in tumor suppressor genes and oncogenes or epigenetic factors in the development of cancer.
 ...
PMID:Cyclooxygenase-2 (cox-2) and the inflammogenesis of cancer. 1761 47

Cyclooxygenase (COX) 2-derived prostaglandin E(2) (PGE(2)) promotes colorectal carcinoma growth and invasion, and inhibition of COX2 by non-steroidal anti-inflammatory drugs is known to inhibit these processes. There is controversy regarding the effect of ligand activation of peroxisome proliferator-activated receptor (PPAR)-beta/delta on colon carcinogenesis, although collective evidence from independent laboratories suggest that ligand activation of PPARbeta/delta leads to the induction of terminal differentiation coupled with inhibition of cell growth in a variety of models. The present study examined the hypothesis that ligand activation of PPARbeta/delta and inhibition of COX2 attenuate colon cancer through independent mechanisms and that combining these two mechanisms will enhance this inhibition. Colon cancer was induced by administering azoxymethane to wild-type and PPARbeta/delta-null mice. Cohorts of mice were treated with GW0742 (a PPARbeta/delta ligand), nimesulide (a COX2 inhibitor) or a combination of GW0742 and nimesulide. Inhibition of COX2 by nimesulide attenuated colon cancer and ligand activation of PPARbeta/delta by GW0742 had inhibitory effects. However, the combined treatment of GW0742 and nimesulide did not cause an enhancement in the attenuation of colon cancer. Mechanistically, the effects of these compounds occurred through independent mechanisms as increased levels of differentiation markers as a result of ligand activation of PPARbeta/delta were not found with COX2 inhibition, and a reduction in PGE(2) levels resulting from COX2 inhibition was not observed in response to ligand activation of PPARbeta/delta. Results from these studies effectively dissociate COX2 inhibition and PPARbeta/delta activity during colon carcinogenesis.
Carcinogenesis 2008 Jan
PMID:Ligand activation of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) and inhibition of cyclooxygenase 2 (COX2) attenuate colon carcinogenesis through independent signaling mechanisms. 1789 32


1 2 3 4 5 Next >>