Effects of the lactase 13910 C/T and calcium-sensor receptor A986S G/T gene polymorphisms on the incidence and recurrence of colorectal cancer in Hungarian population

Background: Epidemiological studies suggested the chemopreventive role of higher calcium intake in colorectal carcinogenesis. We examined genetic polymorphisms that might influence calcium metabolism: lactase (LCT) gene 13910 C/T polymorphism causing lactose intolerance and calcium-sensing receptor (CaSR) gene A986S polymorphism as a responsible factor for the altered cellular calcium sensation. Methods: 538 Hungarian subjects were studied: 278 patients with colorectal cancer and 260 healthy controls. Median follow-up was 17 months. After genotyping, the relationship between LCT 13910 C/T and CaSR A986S polymorphisms as well as tumor incidence/progression was investigated. Results: in patient with colorectal cancer, a significantly higher LCT CC frequency was associated with increased distant disease recurrence (OR = 4.04; 95% CI = 1.71-9.58; p = 0.006). The disease free survival calculated from distant recurrence was reduced for those with LCT CC genotype (log rank test p = 0.008). In case of CaSR A986S polymorphism, the homozygous SS genotype was more frequent in patients than in controls (OR = 4.01; 95% CI = 1.33-12.07; p = 0.014). The number of LCT C and CaSR S risk alleles were correlated with tumor incidence (p = 0.035). The CCSS genotype combination was found only in patients with CRC (p = 0.033). Conclusion: LCT 13910 C/T and CaSR A986S polymorphisms may have an impact on the progression and/or incidence of CRC

Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells

<p>Abstract</p> <p>Background</p> <p>The progression from Barrett's metaplasia to adenocarcinoma is associated with the acquirement of an apoptosis-resistant phenotype. The bile acid deoxycholate (DCA) has been proposed to play an important role in the development of esophageal adenocarcinoma, but the precise molecular mechanisms remain undefined. The aim of this study was to investigate DCA-stimulated COX-2 signaling pathways and their possible contribution to deregulated cell survival and apoptosis in esophageal adenocarcinoma cells.</p> <p>Methods</p> <p>Following exposure of SKGT-4 cells to DCA, protein levels of COX-2, MAPK and PARP were examined by immunoblotting. AP-1 activity was assessed by mobility shift assay. DCA-induced toxicity was assessed by DNA fragmentation and MTT assay.</p> <p>Results</p> <p>DCA induced persistent activation of the AP-1 transcription factor with Fra-1 and JunB identified as the predominant components of the DCA-induced AP-1 complex. DCA activated Fra-1 via the Erk1/2- and p38 MAPK while Erk1/2 is upstream of JunB. Moreover, DCA stimulation mediated inhibition of proliferation with concomitant low levels of caspase-3-dependent PARP cleavage and DNA fragmentation. Induction of the anti-apoptotic protein COX-2 by DCA, via MAPK/AP-1 pathway appeared to balance the DCA mediated activation of pro-apoptotic markers such as PARP cleavage and DNA fragmentation. Both of these markers were increased upon COX-2 suppression by aspirin pretreatment prior to DCA exposure.</p> <p>Conclusion</p> <p>DCA regulates both apoptosis and COX-2-regulated cell survival in esophageal cells suggesting that the balance between these two opposing signals may determine the transformation potential of DCA as a component of the refluxate.</p

Mechanisms of the intestinal effects of dietary fats and milk products on colon carcinogenesis

Dietary fat may promote colon cancer by increasing fatty acids (FA) and secondary bile acids (BA) in the colonic lumen. These cytotoxic surfactants can damage colonic epithelial cells and thus induce a compensatory hyperproliferation of crypt Cells. Our studies show that the hyperproliferative effect of type and amount of dietary fat is not simply due to changes in colonic FA and BA. This indicates that an additional, at present unknown, cytotoxic factor is involved. The hyperproliferative effect of dietary fat is inversely related to the amount of calcium in the diet. In rat and man, dietary calcium precipitates colonic cytotoxic surfactants and thus inhibits luminal cytotoxicity. These inhibitory effects on metabolic risk factors suggest a preventive effect of dietary calcium on colon carcinogenesis. (C) 1997 Elsevier Science Ireland Ltd

Calcium in milk products precipitates intestinal fatty acids and secondary bile acids and thus inhibits colonic cytotoxicity in humans

Dietary calcium may reduce the risk of colon cancer, probably by precipitating cytotoxic surfactants, such as secondary bile acids, in the colonic lumen. We previously showed that milk mineral, an important source of calcium, decreases metabolic risk factors and colonic proliferation in rats, We non report the effects of the habitual intake of milk calcium on metabolic risk factors in healthy subjects. A double-blind, cross-over metabolic study was performed in 13 healthy males, Placebo milk products (calcium, 3 mM) were compared with regular milk products (calcium, 30 mM), In each 1-week period, the habitual diet was recorded, and urine and feces were collected for 1 and 3 days, respectively. Milk calcium significantly increased fecal pH and fecal excretion of phosphate (132%), total fat (139%), free fatty acids (195%), and bile acids (141%), indicating intestinal complexation. In fecal water, the concentrations of long-chain fatty acids, secondary bile acids (deoxycholic and lithocholic acid), neutral sterols, and phospholipids were about halved (P <0.05), Consistent with these changes in soluble hydrophobic surfactants, calcium decreased the cytotoxicity of fecal crater from 68 +/- 9 to 28 +/- 12% (P <0.005), Calcium in milk products precipitates luminal cytotoxic surfactants and thus inhibits colonic cytotoxicity. Therefore, habitual dietary calcium may contribute to a nutritional modulation of colon cancer risk

MECHANISM OF THE PROTECTIVE EFFECT OF SUPPLEMENTAL DIETARY CALCIUM ON CYTOLYTIC ACTIVITY OF FECAL WATER

Dietary calcium supplementation inhibits hyperproliferation of rectal epithelium, possibly by precipitating luminal surfactants and thus preventing their cell-damaging effects. Therefore, we studied the effects of supplemental dietary calcium (35.5 mmol/day) on composition and cytolytic activity of fecal water and on the release of the epithelial marker alkaline phosphatase in 12 healthy volunteers. Fecal water was isolated by low-speed centrifugation. Cytolytic activity was determined as lysis of human erythrocytes by fecal water. Intestinal alkaline phosphatase activity in fecal water was measured with the use of the uncompetitive inhibitor L-phenylalanine. Supplemental calcium increased soluble calcium and decreased soluble P(i). The logarithm of the concentration product of calcium and phosphate was linearly dependent on pH. These observations indicate formation of insoluble calcium phosphate. Supplemental calcium did not alter the total bile acid concentration in fecal water but significantly decreased the ratio of more hydrophobic to more hydrophilic bile acids from 3.3 to 2.3. Calcium also significantly decreased the concentration of fatty acids (from 2.9 to 2.1 mm). Consistent with these decreases in hydrophobic surfactants, calcium decreased the cytolytic activity of fecal water from 47 +/- 9 to 27 +/- 8% (n = 12, P <0.05). Analogous to the decrease in cytolytic activity, the release of the epithelial marker alkaline phosphatase was also lowered by supplemental calcium. We conclude that supplemental dietary calcium decreases luminal cytotoxic surfactant concentrations and thus inhibits luminal cytolytic activity and the release of the epithelial marker alkaline phosphatase as an indicator of intestinal epitheliolysis. This mechanism may explain how dietary calcium could decrease epithelial cell proliferation