Abstract
Colorectal cancer (CRC) risk is modulated by diet and there is convincing evidence of reduced risk with higher non‐digestible carbohydrates (NDCs) consumption. Resistant starch (RS), a NDC, positively modulates the expression of oncogenic microRNAs, suggesting that this could be a mechanism through which NDCs protect against CRC. The present study aimed to investigate the effects of supplementation with two NDCs, RS, and polydextrose (PD), on microRNA expression in the macroscopically‐normal human rectal epithelium using samples from the DISC Study, a randomized, double‐blind, placebo‐controlled dietary intervention. We screened 1008 miRNAs in pooled post‐intervention rectal mucosal samples from participants allocated to the double placebo group and those supplemented with both RS and PD. A total of 111 miRNAs were up‐ or down‐regulated by at least twofold in the RS + PD group compared with the control group. From these, eight were selected for quantification in individual participant samples by qPCR, and fold‐change direction was consistent with the array for seven miRNAs. The inconsistency for miR‐133b and the lower fold‐change values observed for the seven miRNAs is probably because qPCR of individual participant samples is a more robust and sensitive method of quantification than the array. miR‐32 expression was increased by approximately threefold (P = 0.033) in the rectal mucosa of participants supplemented with RS + PD compared with placebo. miR‐32 is involved in the regulation of processes such as cell proliferation that are dysregulated in CRC. Furthermore, miR‐32 may affect non‐canonical NF‐κB signaling via regulation of TRAF3 expression and consequently NIK stabilization.
Highlights
Colorectal cancer (CRC) is the third most common cancer worldwide and fourth most common cause of cancer-related death.[1]
MiRNAs regulate the expression of thousands of genes by inhibiting their expression and, have effects on many biological processes including those involved in tumorigenesis.[7,15,18]
Abnormal expression of miRNAs is implicated in the pathogenesis of CRC, where it is associated with disease progression, treatment response, and prognosis.[19,20] miRNAs have potential to be used as cancer biomarkers since altered expression is observed in colorectal tissue and in the plasma, stool, and urine from CRC patients.[11,12]
Summary
Colorectal cancer (CRC) is the third most common cancer worldwide and fourth most common cause of cancer-related death.[1]. Hu et al reported that butyrate exposure altered expression of 44 miRNAs in HCT-116 cells, 18 of which were confirmed by qPCR.[7] Humphreys et al were the first to investigate the effects of RS and butyrate on expression of miR-17-92 cluster members in a human intervention study.[15] Supplementation of a high red meat diet, which increased miR-17-92 expression by approximately 30%, with butyrylated RS for 4 wk restored expression to baseline levels, suggesting that RS reversed the detrimental effects of red meat on expression of oncogenic miRNAs. In the current study, we hypothesised that NDCs are protective against CRC by regulating the expression of miRNAs, in particular by down-regulating expression of miRNAs that are upregulated in CRC. We validated the findings from the miRNome array for eight miRNAs by qPCR using RNA samples from 29 individual participants
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