RRC ID 61281
Author Chen Y, Sun Y, Rao Q, Xu H, Li L, Chang C.
Title Androgen receptor (AR) suppresses miRNA-145 to promote renal cell carcinoma (RCC) progression independent of VHL status.
Journal Oncotarget
Abstract 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 HIF2α/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 HIF2α/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.
Volume 6(31)
Pages 31203-15
Published 2015-10-13
DOI 10.18632/oncotarget.4522
PII 4522
PMID 26304926
PMC PMC4741598
MeSH Animals Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / metabolism Binding Sites Carcinoma, Renal Cell / genetics Carcinoma, Renal Cell / metabolism* Carcinoma, Renal Cell / pathology Carcinoma, Renal Cell / therapy Cell Line, Tumor Cell Movement Cell Proliferation Cyclin D1 / genetics Cyclin D1 / metabolism Disease Progression Down-Regulation Gene Expression Regulation, Neoplastic Humans Kidney Neoplasms / genetics Kidney Neoplasms / metabolism* Kidney Neoplasms / pathology Kidney Neoplasms / therapy Male Matrix Metalloproteinase 9 / genetics Matrix Metalloproteinase 9 / metabolism Mice, Nude MicroRNAs / genetics MicroRNAs / metabolism* Mutation Neoplasm Invasiveness Promoter Regions, Genetic RNA Interference RNAi Therapeutics Receptors, Androgen / genetics Receptors, Androgen / metabolism* Signal Transduction Time Factors Transfection Vascular Endothelial Growth Factor A / genetics Vascular Endothelial Growth Factor A / metabolism Von Hippel-Lindau Tumor Suppressor Protein / genetics* Xenograft Model Antitumor Assays
IF 5.168
Human and Animal Cells OS-RC-2(RCB0735)