Abstract
Colonic microbiota ferment non-absorbed dietary fiber to produce prodigious amounts of short chain fatty acids (SCFAs) that benefit the host through a myriad of metabolic, trophic, and chemopreventative effects. The chemopreventative effects of the SCFA butyrate are, in part, mediated through induction of p21 gene expression. In this study, we assessed the role of microRNA(miRNA) in butyrate's induction of p21 expression. The expression profiles of miRNAs in HCT-116 cells and in human sporadic colon cancers were assessed by microarray and quantitative PCR. Regulation of p21 gene expression by miR-106b was assessed by 3′ UTR luciferase reporter assays and transfection of specific miRNA mimics. Butyrate changed the expression of 44 miRNAs in HCT-116 cells, many of which were aberrantly expressed in colon cancer tissues. Members of the miR-106b family were decreased in the former and increased in the latter. Butyrate-induced p21 protein expression was dampened by treatment with a miR-106b mimic. Mutated p21 3′UTR-reporter constructs expressed in HCT-116 cells confirmed direct miR-106b targeting. Butyrate decreased HCT-116 proliferation, an effect reversed with the addition of the miR-106b mimic. We conclude that microbe-derived SCFAs regulate host gene expression involved in intestinal homeostasis as well as carcinogenesis through modulation of miRNAs.
Highlights
Most human sporadic colon cancers develop gradually as accumulating alterations in gene expression transform normal colonic epithelium to adenocarcinoma
Among the proposed dietary risk factors is low fiber content, which may lower the bioavailability of short chain fatty acids (SCFAs) that are formed by microbial anaerobic fermentation of dietary fiber [2]
These microbial products provide an important source of energy to the colonic epithelium, and have widespread trophic effects that include regulation of host genes involved in maintenance of intestinal homeostasis [4]
Summary
Most human sporadic colon cancers develop gradually as accumulating alterations in gene expression transform normal colonic epithelium to adenocarcinoma. SCFAs such as acetate, proprionate, and butyrate are produced in prodigious amounts and are the most abundant anions in colonic luminal fluid and feces [3]. These microbial products provide an important source of energy to the colonic epithelium, and have widespread trophic effects that include regulation of host genes involved in maintenance of intestinal homeostasis [4]. Amongst the genes altered by butyrate treatment were many involved in cell cycle regulation, such as the cyclin dependent kinase inhibitor p21, GADD45A, and PTEN [6]
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