Browsing ECNIS annotated biomarkers bibliographic database - test version by Journal
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Obesity and colorectal cancer: epidemiology, mechanisms and candidate genes.There is increasing evidence that dysregulation of energy homeostasis is associated with colorectal carcinogenesis. Epidemiological data have consistently demonstrated a positive relation between increased body size and colorectal malignancy, whereas mechanistic studies have sought to uncover obesity-related carcinogenic pathways. The phenomenon of "insulin resistance" or the impaired ability to normalize plasma glucose levels has formed the core of these pathways, but other mechanisms have also been advanced. Obesity-induced insulin resistance leads to elevated levels of plasma insulin, glucose and fatty acids. Exposure of the colonocyte to heightened concentrations of insulin may induce a mitogenic effect within these cells, whereas exposure to glucose and fatty acids may induce metabolic perturbations, alterations in cell signaling pathways and oxidative stress. The importance of chronic inflammation in the pathogenesis of obesity has recently been highlighted and may represent an additional mechanism linking increased adiposity to colorectal carcinogenesis. This review provides an overview of the epidemiology of body size and colorectal neoplasia and outlines current knowledge of putative mechanisms advanced to explain this relation. Family based studies have shown that the propensity to become obese is heritable, but this is only manifest in conditions of excess energy intake over expenditure. Inheritance of a genetic profile that predisposes to increased body size may also be predictive of colorectal cancer. Genomewide scans, linkage studies and candidate gene investigations have highlighted more than 400 chromosomal regions that may harbor variants that predispose to increased body size. The genetics underlying the pathogenesis of obesity are likely to be complex, but variants in a range of different genes have already been associated with increased body size and insulin resistance. These include genes encoding elements of insulin signaling, adipocyte metabolism and differentiation, and regulation of energy expenditure. A number of investigators have begun to study genetic variants within these pathways in relation to colorectal neoplasia, but at present data remain limited to a handful of studies. These pathways will be discussed with particular reference to genetic polymorphisms that have been associated with obesity and insulin resistance.
Phenylethyl isothiocyanate and its N-acetylcysteine conjugate suppress the metastasis of SK-Hep1 human hepatoma cells.Phenylethyl isothiocyanate (PEITC), a hydrolysis compound of gluconasturtiin, is metabolized to N-acetylcysteine (NAC)-PEITC in the body after the consumption of cruciferous vegetables. We observed an inhibitory effect of PEITC and its metabolite NAC-PEITC on cancer cell proliferation, adhesion, invasion, migration and metastasis in SK-Hep1 human hepatoma cells. PEITC and NAC-PEITC suppressed SK-Hep1 cell proliferation in a dose-dependent manner, and exposure to 10 microM PEITC or NAC-PEITC reduced cell proliferation by 25% and 30%, respectively. NAC-PEITC inhibited cancer cell adhesion, invasion and migration to a similar or to an even larger degree than PEITC. The expression of matrix metalloproteinase (MMP) 2, MMP-9 and membrane type 1 matrix metalloproteinase (MT1-MMP) is a known risk factor for metastatic disease. Gelatin zymography analysis revealed a significant downregulation of MMP-2/MMP-9 protein expression in SK-Hep1 cells treated with 0.1-5 microM PEITC or NAC-PEITC. PEITC and NAC-PEITC treatment caused dose-dependent decreases in MMP-2/MMP-9 and MT1-MMP mRNA levels, as determined by reverse transcription polymerase chain reaction. PEITC and NAC-PEITC also increased the mRNA levels of tissue inhibitors of matrix metalloproteinase (TIMPs) 1 and 2. Our data suggest that this inhibition is mediated by downregulation of MMP and upregulation of TIMPs.