title: Androgen receptor (AR) signaling promotes RCC progression via increased endothelial cell proliferation and recruitment by modulating AKT → NF-κB → CXCL5 signaling.
abstract: Androgen receptor (AR) signaling may promote renal cell carcinoma (RCC) progression via altered HIF-2α/VEGF signaling. However, it remains unclear whether AR signaling also promotes RCC progression by recruiting vascular endothelial cells (ECs), key players in the development of blood vessels. In our study, AR increased EC proliferation and recruitment to the tumor microenvironment and promoted RCC progression. Mechanistically, AR modulated cytokine CXCL5 expression by altering AKT → NF-κB signaling, and interruption of AKT → NF-κB → CXCL5 signaling using either specific inhibitors or siRNA suppressed AR-enhanced EC recruitment and AR-EC-promoted RCC progression. The results obtained using an in vivo mouse model and a human clinical sample survey confirmed the role of AR in promoting RCC progression through enhancement of EC proliferation and/or recruitment via altered AKT → NF-κB → CXCL5 signaling. Targeting this newly identified AR-induced AKT → NF-κB → CXCL5 pathway may facilitate the development of new therapies for slowing RCC progression.
authors.affiliation: Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Core Facility for Protein Research, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|Beijing Jianlan Institute of Medicine, Beijing 100190, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Jinhai
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Dalin
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054365:Chemokine CXCL5 / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: C486263:CXCL5 protein, human; D054365:Chemokine CXCL5; D016328:NF-kappa B; D011944:Receptors, Androgen; D051057:Proto-Oncogene Proteins c-akt