Non‐digestible carbohydrates supplementation increases miR‐32 expression in the healthy human colorectal epithelium: A randomized controlled trial

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.

Genetic Alterations of TRAF Proteins in Human Cancers

“…In line with the in vivo data, mutations and deletions of TRAF3 are detected in 2.3% (10/439) of human colon cancers (TCGA, PanCancer Atlas). Furthermore, miR-32-TRAF3-mediated inhibition of the NIK-NF-κB2 pathway protects human colorectal epithelium against colorectal cancer in response to a diet of non-digestible carbohydrates ( 181 ). Thus, TRAF3 appears to act in both epithelial cells and myeloid cells to suppress colon tumorigenesis by inhibiting the NF-κB2 and TLR-induced inflammatory pathways.…”

Mechanisms underlying the effects of nutrition, adiposity and physical activity on colorectal cancer risk

“…We have shown that in the macroscopically normal colorectum of healthy participants, supplementation with non‐digestible carbohydrates (a source of butyrate) for 7 weeks significantly increased the expression of miR‐32 , involved in the regulation of cell proliferation levels (Malcomson et al . 2017b). Furthermore, resistant starch significantly reduced the expression of CTNNB1 and c‐MYC , as well as SFRP1, suggesting further protective effects of dietary fibre via effects on WNT signalling (Malcomson et al .…”

miR-17-92 functions as an oncogene and modulates NF-κB signaling by targeting TRAF3 in MGC-803 human gastric cancer cells

“…As a matter of fact, TRAF3 can be regulated by various miRNAs. For example, TRAF3 has been demonstrated to be targeted by miR-32 to affect non-canonical NF-κB signaling and consequently, NIK stabilization (52). TRAF3 is also directly targeted by miR-214-3p to promote osteoclast-and bone-resorbing activity (53).…”