title: Dietary manipulation of oncogenic microRNA expression in human rectal mucosa: a randomized trial.
abstract: High red meat (HRM) intake is associated with increased colorectal cancer risk, while resistant starch is probably protective. Resistant starch fermentation produces butyrate, which can alter microRNA (miRNA) levels in colorectal cancer cells in vitro; effects of red meat and resistant starch on miRNA expression in vivo were unknown. This study examined whether a HRM diet altered miRNA expression in rectal mucosa tissue of healthy volunteers, and if supplementation with butyrylated resistant starch (HRM+HAMSB) modified this response. In a randomized cross-over design, 23 volunteers undertook four 4-week dietary interventions; an HRM diet (300 g/day lean red meat) and an HRM+HAMSB diet (HRM with 40 g/day butyrylated high amylose maize starch), preceded by an entry diet and separated by a washout. Fecal butyrate increased with the HRM+HAMSB diet. Levels of oncogenic mature miRNAs, including miR17-92 cluster miRNAs and miR21, increased in the rectal mucosa with the HRM diet, whereas the HRM+HAMSB diet restored miR17-92 miRNAs, but not miR21, to baseline levels. Elevated miR17-92 and miR21 in the HRM diet corresponded with increased cell proliferation, and a decrease in miR17-92 target gene transcript levels, including CDKN1A. The oncogenic miR17-92 cluster is differentially regulated by dietary factors that increase or decrease risk for colorectal cancer, and this may explain, at least in part, the respective risk profiles of HRM and resistant starch. These findings support increased resistant starch consumption as a means of reducing risk associated with an HRM diet.
authors.affiliation: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia. karen.humphreys@flinders.edu.au richard.leleu@csiro.au.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Humphreys
authors.affiliation: Preventative Health National Research Flagship, CSIRO, and CSIRO Animal, Food and Health Sciences, Adelaide, South Australia, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Conlon
authors.affiliation: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.
authors.forename: Graeme P
authors.initials: GP
authors.lastname: Young
authors.affiliation: Preventative Health National Research Flagship, CSIRO, and CSIRO Animal, Food and Health Sciences, Adelaide, South Australia, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Topping
authors.affiliation: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Winter
authors.affiliation: Preventative Health National Research Flagship, CSIRO, and CSIRO Animal, Food and Health Sciences, Adelaide, South Australia, Australia.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Bird
authors.affiliation: Preventative Health National Research Flagship, CSIRO, and CSIRO Animal, Food and Health Sciences, Adelaide, South Australia, Australia.
authors.forename: Lynne
authors.initials: L
authors.lastname: Cobiac
authors.affiliation: Department of Gastroenterology, Flinders Medical Centre, Adelaide, South Australia, Australia.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Kennedy
authors.affiliation: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.
authors.forename: Michael Z
authors.initials: MZ
authors.lastname: Michael
authors.affiliation: Preventative Health National Research Flagship, CSIRO, and CSIRO Animal, Food and Health Sciences, Adelaide, South Australia, Australia. karen.humphreys@flinders.edu.au richard.leleu@csiro.au.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Le Leu
mesh_terms: D000368:Aged; D000688:Amylose / Q000737:chemistry; D000818:Animals; D001628:Beverages; D001706:Biopsy; D049109:Cell Proliferation; D002957:Citrus; D016000:Cluster Analysis; D018592:Cross-Over Studies; D004032:Diet; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000382:microbiology*; D008297:Male; D008460:Meat; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D008892:Milk; D005810:Multigene Family; D062085:RNA, Long Noncoding; D012004:Rectal Neoplasms / Q000378:metabolism*; D013213:Starch; D003313:Zea mays
chemical_list: C568997:MIR17HG, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D013213:Starch; D000688:Amylose