Aberrant promoter methylation of p16 in colorectal adenocarcinoma in North Indian patients

AIM:To investigate p16 gene methylation and its expression in 30 patients with sporadic colorectal adenocarcinoma in a North Indian population. METHODS:Methylation specific polymerase chain reaction was used to detect p16 gene methylation and immunohistochemistry was used to study the p16 expression in 30 sporadic colorectal tumors as well as adjoining and normal tissue specimens.RESULTS:Aberrant promoter methylation of p16 gene was detected in 12(40%)tumor specimens,whereas no promoter methylation was observed in adjoining and normal tissue.Immunohistochemistry showed expression of p16 protein in 26(86.6%)colorectal tumors whereas complete loss of expression was seen in 4(13.3%)and reduced expression was observed in 12(40%)tumors. In the adjoining mucosa,expression of p16 was in 11 (36.6%)whereas no clear positivity for p16 protein was seen in normal tissue.There was a significant difference in the expression of p16 protein in tumor tissue and adjoining mucosa(P<0.001).The methylation of the p16 gene had a significant effect on the expression of p16 protein(P=0.021).There was a significant association of methylation of p16 gene with the tumor size (P=0.015)and of the loss/reduced expression of p16 protein with the proximal site of the tumor(P=0.047). Promoter methylation and expression of p16 had no relation with the survival of the patients(P>0.05). CONCLUSION:Our study demonstrated that promoter hypermethylation of the p16 gene results in loss/reduced expression of p16 protein and this loss/reduced expression may contribute to tumor enlargement.

Bile acid receptors and gastrointestinal functions

Bile acids modulate several gastrointestinal(GI)functions including electrolyte secretion and absorption,gastric emptying,and small intestinal and colonic motility.High concentrations of bile acids lead to diarrhea and are implicated in the development of esophageal,gastric and colonic cancer.Alterations in bile acid homeostasis are also implicated in the pathophysiology of irritable bowel syndrome(IBS)and inflammatory bowel disease(IBD).Our understanding of the mechanisms underlying these effects of bile acids on gut functions has been greatly enhanced by the discovery of bile acid receptors,including the nuclear receptors:farnesoid X receptor(FXR),vitamin D receptor(VDR),pregnane X receptor(PXR),and constitutive androstane receptor(CAR);and G protein-coupled receptors(GPCRs):Takeda G protein-coupled receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and muscarinic acetylcholine receptor M3(M3R).For example,various studies provided evidence demonstrating the anti-inflammatory effects of FXR and TGR5 activation in models of intestinal inflammation.In addition,the activation of TGR5 in enteric neurons was recently shown to increase colonic motility,which may lead to bile acid-induced diarrhea(BAD).Interestingly,TGR5 induces the secretion of glucagon-like peptide-1(GLP-1)from L-cells to enhance insulin secretion and modulate glucose metabolism.Because of the importance of these receptors,agonists of TGR5 and intestine-specific FXR agonists are currently being tested as an option for the treatment of diabetes mellitus and primary bile acid diarrhea,respectively.This review summarizes current knowledge of the functional roles of bile acid receptors in the GI tract.