Carcinogenesis

About: Carcinogenesis is a research topic. Over the lifetime, 60368 publications have been published within this topic receiving 3192599 citations. The topic is also known as: oncogenesis & tumorigenesis.

Accelerated age-related CpG island methylation in ulcerative colitis.

Abstract: CpG island hypermethylation is a mechanism of gene silencing that can be usurped by neoplastic cells to inactivate undesirable genes. In the colon, hypermethylation often starts in normal mucosa as a function of age and is markedly increased in cancer. To test the hypothesis that subjects at increased risk of colon cancer have higher levels of methylation in their nonneoplastic mucosa, we studied methylation patterns of five genes in the normal and dysplastic mucosa of patients with ulcerative colitis (UC), a condition associated with a marked increased risk of colon cancer. One gene ( Mlh1 ) was unmethylated in all tissues examined. All four remaining genes had low but detectable levels of methylation in the epithelium of UC patients without evidence of dysplasia, and this methylation was not different from non-UC controls. By contrast, all four genes were highly methylated in dysplastic epithelium from high-grade dysplasia (HGD)/cancer patients with UC; methylation in HGD versus controls averaged 40.0% versus 7.4% ( P = 0.00003) for ER , 44.0% versus 3.0% ( P MYOD , 9.4% versus 2.4% ( P = 0.03) for p16 exon 1, and 57.5% versus 30.6% ( P = 0.01) for CSPG2 . Importantly, three of the four genes were also highly methylated in the normal appearing (nondysplastic) epithelium from these same HGD/cancer patients, indicating that methylation precedes dysplasia and is widespread in these patients. Compared with controls, methylation averaged 20.1% versus 7.2% ( P = 0.07) for ER , 18.4% versus 3.0% ( P MYOD , and 7.9% versus 2.4% ( P = 0.007) for p16 exon 1. These results are consistent with the hypothesis that age-related methylation marks (and may lead to) the field defect that reflects acquired predisposition to colorectal neoplasia. Furthermore, the data suggest that chronic inflammation is associated with high levels of methylation, perhaps as a result of increased cell turnover, and that UC can be viewed as resulting in premature aging of colorectal epithelial cells.

Gene expression signature of cigarette smoking and its role in lung adenocarcinoma development and survival.

Abstract: Background: Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure. Methodology/Principal Findings: We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p,0.001 and fold-change .1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p,0.001) and TTK (p=0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers. Conclusions/Significance: Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers.

IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis.

Abstract: SPECIFIC AIMThere is growing evidence that inflammation is a contributing factor leading to cancer development, yet pathways involved in this progression are not well understood. While HIF-1, a heterodimeric transcription factor composed of inducibly expressed HIF-1α and constitutively expressed HIF-1β, regulates genes that play essential roles in tumor progression and HIF-1 activity is up-regulated in inflammatory conditions, there is no prior evidence suggesting a role for HIF-1 as a link between inflammation and the development of cancer. Therefore, we investigated whether the HIF-1 signaling pathway was stimulated by the proinflammatory cytokine interleukin-1 β (IL-1β) -induced inflammatory signal in A549 cells.PRINCIPAL FINDINGS1. HIF-1α induction by IL-1β is mediated by NFκBTo test whether IL-1β was able to induce HIF-1α protein, we treated the lung epithelial cell line A549 with IL-1β under normoxia. HIF-1α protein was markedly induced by IL-1β. Because the proinflammatory cytokine IL-1β activates ...