Androgen receptor increases hematogenous metastasis yet decreases lymphatic metastasis of renal cell carcinoma

Nat Commun. 2017 Oct 13;8(1):918. doi: 10.1038/s41467-017-00701-6.

Abstract

Clear cell renal cell carcinoma (ccRCC) is a gender-biased tumor. Here we report that there is also a gender difference between pulmonary metastasis and lymph node metastasis showing that the androgen receptor (AR)-positive ccRCC may prefer to metastasize to lung rather than to lymph nodes. A higher AR expression increases ccRCC hematogenous metastasis yet decreases ccRCC lymphatic metastases. Mechanism dissection indicates that AR enhances miR-185-5p expression via binding to the androgen response elements located on the promoter of miR-185-5p, which suppresses VEGF-C expression via binding to its 3' UTR. In contrast, AR-enhanced miR-185-5p also promotes HIF2α/VEGF-A expression via binding to the promoter region of HIF2α. Together, these results provide a unique mechanism by which AR can either increase or decrease ccRCC metastasis at different sites and may help us to develop combined therapies using anti-AR and anti-VEGF-C compounds to better suppress ccRCC progression.The incidence of renal cell carcinoma is higher in males than in females due to the different androgen receptor signaling but the molecular mechanisms behind this gender bias are unclear. Here the authors show how androgen receptor expression influences the metastatic route through the regulation of miR-185 and VEGF isoforms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / secondary
  • Cell Line, Tumor
  • Female
  • HEK293 Cells
  • Humans
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Lung / pathology
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Lymphangiogenesis
  • Lymphatic Metastasis*
  • Male
  • Mice, Nude
  • MicroRNAs / metabolism*
  • Neovascularization, Pathologic
  • Receptors, Androgen / metabolism*
  • Sex Factors
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor C / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • MIRN185 microRNA, human
  • MicroRNAs
  • Receptors, Androgen
  • VEGFA protein, human
  • VEGFC protein, human
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • endothelial PAS domain-containing protein 1