Androgen receptor and microRNA-21 axis downregulates transforming growth factor beta receptor II (TGFBR2) expression in prostate cancer
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) si...
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| Veröffentlicht in: | Oncogene 2014-07, Vol.33 (31), p.4097-4106 |
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| creator | Mishra, S Deng, J J Gowda, P S Rao, M K Lin, C-L Chen, C L Huang, T Sun, L-Z |
| description | 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. |
| doi_str_mv | 10.1038/onc.2013.374 |
| format | Article |
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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.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2013.374</identifier><identifier>PMID: 24037531</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>3' Untranslated regions ; 631/337/384/331 ; 631/45/612/822 ; 631/67/581 ; 692/699/67/589/466 ; Androgen receptors ; Androgens ; Animals ; Apoptosis ; Cell activation ; Cell Biology ; Cell Line, Tumor ; Cell migration ; Cell receptors ; Cellular biology ; Development and progression ; Epithelial cells ; Gene Expression Regulation, Neoplastic ; Genetic aspects ; Growth factors ; Human Genetics ; Humans ; Internal Medicine ; Male ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; MicroRNA ; MicroRNAs ; MicroRNAs - metabolism ; miRNA ; Neoplasms, Experimental ; Oncology ; original-article ; Properties ; Prostate cancer ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Receptors, Androgen - metabolism ; Receptors, Transforming Growth Factor beta - genetics ; Receptors, Transforming Growth Factor beta - metabolism ; Smad2 protein ; Transforming growth factor-b ; Tumors ; Xenografts</subject><ispartof>Oncogene, 2014-07, Vol.33 (31), p.4097-4106</ispartof><rights>Macmillan Publishers Limited 2014</rights><rights>COPYRIGHT 2014 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 31, 2014</rights><rights>Macmillan Publishers Limited 2014.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c659t-7f5ab05e9b55471f65754811f820718687b0aeabfd4fea25f7a68a78697916863</citedby><cites>FETCH-LOGICAL-c659t-7f5ab05e9b55471f65754811f820718687b0aeabfd4fea25f7a68a78697916863</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2013.374$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2013.374$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24037531$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mishra, S</creatorcontrib><creatorcontrib>Deng, J J</creatorcontrib><creatorcontrib>Gowda, P S</creatorcontrib><creatorcontrib>Rao, M K</creatorcontrib><creatorcontrib>Lin, C-L</creatorcontrib><creatorcontrib>Chen, C L</creatorcontrib><creatorcontrib>Huang, T</creatorcontrib><creatorcontrib>Sun, L-Z</creatorcontrib><title>Androgen receptor and microRNA-21 axis downregulates transforming growth factor beta receptor II (TGFBR2) expression in prostate cancer</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>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.</description><subject>3' Untranslated regions</subject><subject>631/337/384/331</subject><subject>631/45/612/822</subject><subject>631/67/581</subject><subject>692/699/67/589/466</subject><subject>Androgen receptors</subject><subject>Androgens</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Cell activation</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell receptors</subject><subject>Cellular biology</subject><subject>Development and progression</subject><subject>Epithelial cells</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genetic aspects</subject><subject>Growth factors</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>MicroRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - 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metabolism</topic><topic>miRNA</topic><topic>Neoplasms, Experimental</topic><topic>Oncology</topic><topic>original-article</topic><topic>Properties</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Receptors, Androgen - metabolism</topic><topic>Receptors, Transforming Growth Factor beta - genetics</topic><topic>Receptors, Transforming Growth Factor beta - metabolism</topic><topic>Smad2 protein</topic><topic>Transforming growth factor-b</topic><topic>Tumors</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mishra, S</creatorcontrib><creatorcontrib>Deng, J J</creatorcontrib><creatorcontrib>Gowda, P S</creatorcontrib><creatorcontrib>Rao, M K</creatorcontrib><creatorcontrib>Lin, C-L</creatorcontrib><creatorcontrib>Chen, C L</creatorcontrib><creatorcontrib>Huang, T</creatorcontrib><creatorcontrib>Sun, L-Z</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mishra, S</au><au>Deng, J J</au><au>Gowda, P S</au><au>Rao, M K</au><au>Lin, C-L</au><au>Chen, C L</au><au>Huang, T</au><au>Sun, L-Z</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Androgen receptor and microRNA-21 axis downregulates transforming growth factor beta receptor II (TGFBR2) expression in prostate cancer</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2014-07-31</date><risdate>2014</risdate><volume>33</volume><issue>31</issue><spage>4097</spage><epage>4106</epage><pages>4097-4106</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24037531</pmid><doi>10.1038/onc.2013.374</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 3' Untranslated regions 631/337/384/331 631/45/612/822 631/67/581 692/699/67/589/466 Androgen receptors Androgens Animals Apoptosis Cell activation Cell Biology Cell Line, Tumor Cell migration Cell receptors Cellular biology Development and progression Epithelial cells Gene Expression Regulation, Neoplastic Genetic aspects Growth factors Human Genetics Humans Internal Medicine Male Medicine Medicine & Public Health Mice Mice, Inbred BALB C Mice, Nude MicroRNA MicroRNAs MicroRNAs - metabolism miRNA Neoplasms, Experimental Oncology original-article Properties Prostate cancer Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Receptors, Androgen - metabolism Receptors, Transforming Growth Factor beta - genetics Receptors, Transforming Growth Factor beta - metabolism Smad2 protein Transforming growth factor-b Tumors Xenografts |
| title | Androgen receptor and microRNA-21 axis downregulates transforming growth factor beta receptor II (TGFBR2) expression in prostate cancer |
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