title: 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 transforming growth factor β (TGFβ) by downregulating TGFβ receptors. However, the mechanism by which cancer cells downregulate TGFβ 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 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 downregulating 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.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mishra
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Deng
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Gowda
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Rao
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: C-L
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Chen
authors.affiliation: 1] Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA [2] Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: T
authors.initials: T
authors.lastname: Huang
authors.affiliation: 1] Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA [2] Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: L-Z
authors.initials: LZ
authors.lastname: Sun
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D009374:Neoplasms, Experimental; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011944:Receptors, Androgen / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: C410798:AR protein, human; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D011944:Receptors, Androgen; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
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