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.
Keywords:
HIF2α; androgen receptor; microRNA-145; renal cell carcinoma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Binding Sites
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / metabolism*
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Carcinoma, Renal Cell / pathology
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Carcinoma, Renal Cell / therapy
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Cell Line, Tumor
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Cell Movement
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Cell Proliferation
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Disease Progression
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Down-Regulation
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Gene Expression Regulation, Neoplastic
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Humans
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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism*
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Kidney Neoplasms / pathology
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Kidney Neoplasms / therapy
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Male
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism
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Mice, Nude
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Mutation
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Neoplasm Invasiveness
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Promoter Regions, Genetic
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RNA Interference
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RNAi Therapeutics
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism*
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Signal Transduction
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Time Factors
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Transfection
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Von Hippel-Lindau Tumor Suppressor Protein / genetics*
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Xenograft Model Antitumor Assays
Substances
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AR protein, human
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Basic Helix-Loop-Helix Transcription Factors
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CCND1 protein, human
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MIRN145 microRNA, human
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MicroRNAs
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Receptors, Androgen
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Cyclin D1
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endothelial PAS domain-containing protein 1
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Von Hippel-Lindau Tumor Suppressor Protein
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MMP9 protein, human
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Matrix Metalloproteinase 9
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VHL protein, human