title: Inhibition of microRNA-31-5p protects human colonic epithelial cells against ionizing radiation.
abstract: MicroRNAs (miRNAs), endogenous non-coding small RNAs, are sensitive to environmental changes, and their differential expression is important for adaptation to the environment. However, application of miRNAs as a clinical prognostic or diagnostic tool remains unproven. In this study we demonstrate a chronic/persistent change of miRNAs from the plasma of a colorectal cancer susceptible mouse model (CPC;Apc) about 250 days after exposure to a simulated solar particle event (SPE). Differentially expressed miRNAs were identified compared to unirradiated control mice, including miR-31-5p, which we investigated further. To address the cellular function of miR-31-5p, we transfected a miR-31-5p mimic (sense) or inhibitor (antisense) into immortalized human colonic epithelial cells followed by gamma-irradiation. A miR-31-5p mimic sensitized but a miR-31-5p inhibitor protected colonic epithelial cells against radiation induced killing. We found that the miR-31-5p mimic inhibited the induction of hMLH1 expression after irradiation, whereas the miR-31-5p inhibitor increased the basal level of hMLH1 expression. The miR-31-5p inhibitor failed to modulate radiosensitivity in an hMLH1-deficient HCT116 colon cancer cell line but protected HCT116 3-6 and DLD-1 (both hMLH1-positive) colon cancer cell lines. Our findings demonstrate that miR-31-5p has an important role in radiation responses through regulation of hMLH1 expression. Targeting this pathway could be a promising therapeutic strategy for future personalized anti-cancer radiotherapy.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9039, United States.
authors.forename: Sang Bum
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9039, United States.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9039, United States.
authors.forename: Summer
authors.initials: S
authors.lastname: Barron
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9039, United States. Electronic address: Jerry.Shay@UTSouthwestern.edu.
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
keywords: Human colonic epithelial cells (HCECs); Human mutL homologue-1 (hMLH1); Radioprotection; Solar Particle Event (SPE); miR-31-5p