n -3 Polyunsaturated fatty acids modulate carcinogen-directed non-coding microRNA signatures in rat colon

Abstract

We have hypothesized that dietary modulation of intestinal non-coding RNA [microRNA (miRNA)] expression may contribute to the chemoprotective effects of nutritional bioactives (fish oil and pectin). To fully understand the effects of these agents on the expression of miRNAs, Sprague-Dawley rats were fed diets containing corn oil or fish oil with pectin or cellulose and injected with azoxymethane (AOM, a colon-specific carcinogen) or saline (control). Real-time polymerase chain reaction using miRNA-specific primers and Taq Man probes was carried out to quantify effects on miRNA expression in colonic mucosa. From 368 mature miRNAs assayed, at an early stage of cancer progression (10 week post AOM injection), let-7d, miR-15b, miR-107, miR-191 and miR-324-5p were significantly (P < 0.05) affected by diet x carcinogen interactions. Overall, fish oil fed animals exhibited the smallest number of differentially expressed miRNAs (AOM versus saline treatment). With respect to the tumor stage (34 week post AOM injection), 46 miRNAs were dysregulated in adenocarcinomas compared with normal mucosa from saline-injected animals. Of the 27 miRNAs expressed at higher (P < 0.05) levels in tumors, miR-34a, 132, 223 and 224 were overexpressed at >10-fold. In contrast, the expression levels of miR-192, 194, 215 and 375 were dramatically reduced (< or = 0.32-fold) in adenocarcinomas. These results demonstrate for the first time the utility of the rat AOM model and the novel role of fish oil in protecting the colon from carcinogen-induced miRNA dysregulation.

microRNA-192, -194 and -215 are frequently downregulated in colorectal cancer

“…Moreover, research on the miRNA expression levels in CRC cell lines also provided similar significant results. In previous studies, similar results indicated that miR-192, -194 and -215 were downregulated in CRC cell lines and rat colon tissues (16,26,27). Furthermore, our studies revealed that the increased tumor size in CRC was closely correlated with the low expression of miR-192, -194 and -215.…”

Dietary Manipulation of Oncogenic MicroRNA Expression in Human Rectal Mucosa: A Randomized Trial

“…Several studies have examined the effect of dietary components in other in vivo models. Examination of the miRNA response in rats fed diets containing corn or fish oil with pectin or cellulose and injected with a carcinogen or saline control particularly demonstrated a novel role for fish oil in protecting the colon from carcinogen-induced miRNA dysregulation, rather than a role for fiber (46,47). Shah and colleagues (47) did however demonstrate that various dietary combinations and carcinogen exposure modulated a number of miRNAs, including miR17-92 cluster miRNAs and miR21 (47).…”

Modulation of miRNAs by Natural Agents: Nature’s way of dealing with cancer

“…Carcinogen significantly downregulated of five known tumor suppressor miRNAs, which were reversed upon exposure to n-3 PUFA [133]. Based on transfection experiments in vitro, tumor suppressor protein, PTEN was found to be targeted by oncogenic miR-21 in human colon cancer cells.…”

“…A study by Davidson et al evaluated the chemopreventive effects of n-3-Polyunsaturated fatty acids (n-3 PUFAs) on azoxymethane-induced colon cancer in rats [133] . Carcinogen significantly downregulated of five known tumor suppressor miRNAs, which were reversed upon exposure to n-3 PUFA [133].…”