title: miRNA-95 mediates radioresistance in tumors by targeting the sphingolipid phosphatase SGPP1.
abstract: Radiation resistance poses a major clinical challenge in cancer treatment, but little is known about how microRNA (miR) may regulate this phenomenon. In this study, we used next-generation sequencing to perform an unbiased comparison of miR expression in PC3 prostate cancer cells rendered resistant to fractionated radiation treatment. One miR candidate found to be upregulated by ionizing radiation was miR-95, the enforced expression of which promoted radiation resistance in a variety of cancer cells. miR-95 overexpression recapitulated an aggressive phenotype including increased cellular proliferation, deregulated G2-M checkpoint following ionizing radiation, and increased invasive potential. Using combined in silico prediction and microarray expression analyses, we identified and validated the sphingolipid phosphatase SGPP1, an antagonist of sphingosine-1-phosphate signaling, as a target of miR-95 that promotes radiation resistance. Consistent with this finding, cell treatment with FTY720, a clinically approved small molecule inhibitor of S1P signaling, sensitized miR-95 overexpressing cells to radiation treatment. In vivo assays extended the significance of these results, showing that miR-95 overexpression increased tumor growth and resistance to radiation treatment in tumor xenografts. Furthermore, reduced tumor necrosis and increased cellular proliferation were seen after radiation treatment of miR-95 overexpressing tumors compared with control tumors. Finally, miR-95 expression was increased in human prostate and breast cancer specimens compared with normal tissue. Together, our work reveals miR-95 expression as a critical determinant of radiation resistance in cancer cells.
authors.affiliation: Authors' Affiliations: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre; Departments of Medicine, Medical Biophysics, and Radiation Oncology, University of Toronto; and Ontario Cancer Institute, University Health Network, Toronto, Canada.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Huang
authors.forename: Samira
authors.initials: S
authors.lastname: Taeb
authors.forename: Sahar
authors.initials: S
authors.lastname: Jahangiri
authors.forename: Urban
authors.initials: U
authors.lastname: Emmenegger
authors.forename: Elisa
authors.initials: E
authors.lastname: Tran
authors.forename: Jeff
authors.initials: J
authors.lastname: Bruce
authors.forename: Aruz
authors.initials: A
authors.lastname: Mesci
authors.forename: Elina
authors.initials: E
authors.lastname: Korpela
authors.forename: Danny
authors.initials: D
authors.lastname: Vesprini
authors.forename: C Shun
authors.initials: CS
authors.lastname: Wong
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
authors.forename: Stanley K
authors.initials: SK
authors.lastname: Liu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D034622:RNA Interference; D011836:Radiation Tolerance / Q000235:genetics*
chemical_list: C575854:MIRN95 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C498527:SGPP1 protein, human; D010744:Phosphoric Monoester Hydrolases