抗辐射性
癌症研究
癌症
前列腺癌
生物
小RNA
癌细胞
鞘脂
下调和上调
放射治疗
医学
细胞生物学
内科学
遗传学
生物化学
基因
作者
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
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2013-10-22
卷期号:73 (23): 6972-6986
被引量:136
标识
DOI:10.1158/0008-5472.can-13-1657
摘要
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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