American Association for Cancer Research
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00085472can131657-sup-fig1.pdf (4.31 MB)

Supplementary Figure 1 from miRNA-95 Mediates Radioresistance in Tumors by Targeting the Sphingolipid Phosphatase SGPP1

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posted on 2023-03-30, 21:52 authored by Xiaoyong Huang, Samira Taeb, Sahar Jahangiri, Urban Emmenegger, Elisa Tran, Jeff Bruce, Aruz Mesci, Elina Korpela, Danny Vesprini, C. Shun Wong, Robert G. Bristow, Fei-Fei Liu, Stanley K. Liu

PDF file - 4418K, miR-95 luciferase reporter assay for PC3-control and PC3-miR-95 stable cells.

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ARTICLE 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. Cancer Res; 73(23); 6972–86. ©2013 AACR.

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