TY - JOUR
T1 - Inhibition of microRNA-31-5p protects human colonic epithelial cells against ionizing radiation
AU - Kim, Sang Bum
AU - Zhang, Lu
AU - Barron, Summer
AU - Shay, Jerry W.
N1 - Funding Information:
We thank Dr. Eric R. Fearon (Ann Arbor, Michigan) for providing the colorectal cancer susceptible mouse model ( CPC;Apc ) for these studies. We thank the support team at Brookhaven National Laboratory and NSRL (Upton, NY) for helping with the simulated SPE delivery to mice. This work was performed in laboratories constructed with support from NIH grant C06 RR30414 . This work was supported by NASA Grants # NNX11AC15G , and NNX09AU95G to J.W.S.
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
KW - Human colonic epithelial cells (HCECs)
KW - Human mutL homologue-1 (hMLH1)
KW - MiR-31-5p
KW - Radioprotection
KW - Solar Particle Event (SPE)
UR - http://www.scopus.com/inward/record.url?scp=84901687962&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84901687962&partnerID=8YFLogxK
U2 - 10.1016/j.lssr.2014.02.001
DO - 10.1016/j.lssr.2014.02.001
M3 - Article
C2 - 26432591
AN - SCOPUS:84901687962
SN - 2214-5524
VL - 1
SP - 67
EP - 73
JO - Life Sciences in Space Research
JF - Life Sciences in Space Research
IS - 1
ER -