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

Abstract

Prostate cancer cells escape growth inhibition from TGFβ by down-regulating TGFβ receptors. However, the mechanism by which cancer cells down-regulate TGFβ receptors in prostate is not clear. Here, we showed that coordinated action of miR-21 and androgen receptor (AR) signaling played a critical role in inhibiting TGFβ receptor II (TGFBR2) expression in prostate cancer cells. Our results revealed that miR-21 suppresses TGFBR2 levels by binding to its 3'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 TGFβ-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 down-regulating TGFBR2, hence inhibiting the tumor suppressive activity of TGFβ pathway. Targeting miR-21 alone or in combination with AR may restore the tumor inhibitory activity of TGFβ in prostate cancer.

Androgen receptor and miRNA-126* axis controls follicle-stimulating hormone receptor expression in porcine ovarian granulosa cells

“…In addition, several recent studies showed that AR can indirectly regulate the expression and function of its target gene also via mechanisms involving miRNAs (Ma et al 2013, Lyu et al 2014, Mishra et al 2014, Pasqualini et al 2015. In this study, we found that miR-126* could decrease FSHR expression and increase the rate of apoptosis in pGCs by binding directly to the 3′-UTR of FSHR.…”

“…One downstream target of AR is miR-125b, which represses p53 expression; this miRNA cooperates with AR to synergistically inhibit the p53 function in mGCs (Sen et al 2014). Similarly, Ribas et al (2009) showed that androgen-bound AR up-regulates expression of miR-21, and the AR/miR-21 axis exerts oncogenic effects in prostate tumors by down-regulating TGFBR2 (Mishra et al 2014). Therefore, we concluded that the coordinated action of AR and miR-126* plays a critical role in inhibiting FSHR expression in pGCs.…”

A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer

“…Given that the cell viability changes for both miRNAs were similar to the MDM4 siRNA-positive control, we believe the latter scenario is likely. Besides p53, MDM4 interacts with several other proteins including p21, a cyclin-dependent kinase inhibitor whose expression is associated with reduced proliferation in prostate cancer (Jin et al 2008, Lee & Lu 2011, Peng et al 2013, the transcription factor E2F1, which is known to play a role in cell-cycle regulation in prostate cancer (Strachan et al 2003, Lee et al 2013, the E3 ubiquitin ligase MDM2 that also harbours polymorphisms associated with the risk of prostate cancer (Badciong & Haas 2002 and both Smad3 and Smad4, which are major activating components of the transforming growth factor-b (TGF-b) signalling pathway that has been shown to repress growth in prostate cancer (Kadakia et al 2002, Bjerke et al 2014, Mishra et al 2014. As MDM4 probably plays a role in cancer susceptibility and progression via multiple pathways, further study is required to assess the prostatespecific effects of miRNA-mediated MDM4 levels on each of these pathways.…”

miR-21 Induces Myofibroblast Differentiation and Promotes the Malignant Progression of Breast Phyllodes Tumors

“…2A). Among these differentially expressed miRNAs, three miRNAs, including miR-21, miR-130b, and miR-92a, caught our attention because these miRNAs have been reported to modulate both differentiation and malignant progression of cancer (25)(26)(27)(28)(29)(30).…”