Androgen receptor and microRNA-21 axis downregulates transforming growth factor beta receptor II (TGFBR2) expression in prostate cancer

S. Mishra, J. J. Deng, P. S. Gowda, M. K. Rao, C. L. Lin, C. L. Chen, T. Huang, L. Z. Sun

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Prostate cancer cells escape growth inhibition from transforming growth factor b (TGFb) by downregulating TGFb receptors. However, the mechanism by which cancer cells downregulate TGFb receptors in prostate is not clear. Here, we showed that coordinated action of miR-21 and androgen receptor (AR) signaling had a critical role in inhibiting TGFb receptor II (TGFBR2) expression in prostate cancer cells. Our results revealed that miR-21 suppresses TGFBR2 levels by binding to its 30-UTR and AR signaling further potentiates this effect in both untransformed and transformed human prostate epithelial cells as well as in human prostate cancers. Analysis of primary prostate cancers showed that increased miR-21/AR expression parallel a significantly reduced expression of TGFBR2. Manipulation of androgen signaling or the expression levels of AR or miR-21 negatively altered TGFBR2 expression in untransformed and transformed human prostate epithelial cells, human prostate cancer xenografts and mouse prostate glands. Importantly, we demonstrated that miR-21 and AR regulated each other's expression resulting in a positive feedback loop. Our results indicated that miR-21/AR mediate its tumor-promoting function by attenuating TGFb-mediated Smad2/3 activation, cell growth inhibition, cell migration and apoptosis. Together, these results suggest that the AR and miR-21 axis exerts its oncogenic effects in prostate tumors by downregulating TGFBR2, hence inhibiting the tumor-suppressive activity of TGFb pathway. Targeting miR-21 alone or in combination with AR may restore the tumor inhibitory activity of TGFb in prostate cancer.

Original languageEnglish (US)
Pages (from-to)4097-4106
Number of pages10
JournalOncogene
Volume33
Issue number31
DOIs
StatePublished - Jul 31 2014

Keywords

  • Androgen receptor
  • MicroRNA
  • Prostate cancer
  • Tumor suppressor

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'Androgen receptor and microRNA-21 axis downregulates transforming growth factor beta receptor II (TGFBR2) expression in prostate cancer'. Together they form a unique fingerprint.

  • Cite this