期刊
ONCOTARGET
卷 6, 期 31, 页码 31203-31215出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4522
关键词
renal cell carcinoma; androgen receptor; microRNA-145; HIF2 alpha
资金
- NIH [CA155477, CA156700]
- George Whipple Professorship Endowment
- Taiwan Department of Health Clinical Trial, Research Center of Excellence [DOH99-TD-B-111-004]
- National High Technology Research and Development Program of China (863 Program) [SS2014AA020607]
Mutational inactivation of the VHL tumor suppressor plays key roles in the development of renal cell carcinoma (RCC), and mutated VHL-mediated VEGF induction has become the main target for the current RCC therapy. Here we identified a signal pathway of VEGF induction by androgen receptor (AR)/miRNA-145 as a new target to suppress RCC progression. Mechanism dissection revealed that AR might function through binding to the androgen receptor element (ARE) located on the promoter region of miRNA-145 to suppress p53's ability to induce expression of miRNA-145 that normally suppresses expression of HIF2 alpha/VEGF/MMP9/CCND1. Suppressing AR with AR-shRNA or introducing exogenous miRNA-145 mimic can attenuate RCC progression independent of VHL status. MiR-145 mimic in preclinical RCC orthotopic xenograft mouse model revealed its efficacy in suppression of RCC progression. These results together identified signals by AR-suppressed miRNA-145 as a key player in the RCC progression via regulating HIF2 alpha/VEGF/MMP9/CCND1 expression levels. Blockade of the newly identified signal by AR inhibition or miRNA-145 mimics has promising therapeutic benefit to suppress RCC progression.
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