title: Androgen receptor (AR) suppresses miRNA-145 to promote renal cell carcinoma (RCC) progression independent of VHL status.
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.
authors: Sex Hormone Research Center, Department of Urology, Tongji Medical College/Hospital, Huazhong University of Science and Technology, Wuhan, China.|George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
authors: Yuan
authors: Y
authors: Chen
authors: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
authors: Yin
authors: Y
authors: Sun
authors: Department of Gynaecology and Obstetrics, Tongji Medical College/Hospital, Huazhong University of Science and Technology, Wuhan, China.|George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
authors: Qun
authors: Q
authors: Rao
authors: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
authors: Hua
authors: H
authors: Xu
authors: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
authors: Lei
authors: L
authors: Li
authors: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.|Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan.
authors: Chawnshang
authors: C
authors: Chang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D000067492:RNAi Therapeutics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019938:Cyclin D1; D020780:Matrix Metalloproteinase 9; D035683:MicroRNAs; D011944:Receptors, Androgen; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C410798:AR protein, human; C530104:CCND1 protein, human; C541010:MIRN145 microRNA, human; C467484:VEGFA protein, human; C579270:MMP9 protein, human; C497446:VHL protein, human
keywords: HIF2α; androgen receptor; microRNA-145; renal cell carcinoma