期刊
MOLECULAR ONCOLOGY
卷 12, 期 8, 页码 1324-1341出版社
WILEY
DOI: 10.1002/1878-0261.12328
关键词
ATM; KU-55933; LITAF; miR-106a; prostate cancer; radiation resistance
类别
资金
- Prostate Cancer Canada
- Movember Foundation [RS2014-03, D2013-24, RS2014-01]
- Telus Motorcycle Ride For Dad (Huronia Branch)
- Ministry of Research and Innovation Early Researcher Award
- Ontario Institute for Cancer Research through Government of Ontario
- Terry Fox Research Institute New Investigator Award
- CIHR New Investigator Award
- Strategic Training in Transdisciplinary Radiation Science for the 21st Century (STARS21) training program - Terry Fox Foundation
- Princess Margaret Cancer Centre
- Government of Ontario
- Lawrence, Ila, and William Gifford Scholarship in Radiation Oncology and Surgery
- Queen Elizabeth II Graduate Scholarship in Science and Technology (QEII-GSST) - Sunnybrook Health Sciences Centre, University of Toronto
Recurrence of high-grade prostate cancer after radiotherapy is a significant clinical problem, resulting in increased morbidity and reduced patient survival. The molecular mechanisms of radiation resistance are being elucidated through the study of microRNA (miR) that negatively regulate gene expression. We performed bioinformatics analyses of The Cancer Genome Atlas (TCGA) dataset to evaluate the association between miR-106a and its putative target lipopolysaccharide-induced TNF- factor (LITAF) in prostate cancer. We characterized the function of miR-106a through invitro and invivo experiments and employed transcriptomic analysis, western blotting, and 3UTR luciferase assays to establish LITAF as a bona fide target of miR-106a. Using our well-characterized radiation-resistant cell lines, we identified that miR-106a was overexpressed in radiation-resistant cells compared to parental cells. In the TCGA, miR-106a was significantly elevated in high-grade human prostate tumors relative to intermediate- and low-grade specimens. An inverse correlation was seen with its target, LITAF. Furthermore, high miR-106a and low LITAF expression predict for biochemical recurrence at 5years after radical prostatectomy. miR-106a overexpression conferred radioresistance by increasing proliferation and reducing senescence, and this was phenocopied by knockdown of LITAF. For the first time, we describe a role for miRNA in upregulating ATM expression. LITAF, not previously attributed to radiation response, mediates this interaction. This route of cancer radioresistance can be overcome using the specific ATM kinase inhibitor, KU-55933. Our research provides the first report of miR-106a and LITAF in prostate cancer radiation resistance and high-grade disease, and presents a viable therapeutic strategy that may ultimately improve patient outcomes.
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