Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis
Bone metastasis is the hallmark of progressive and castration-resistant prostate cancers. MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that S...
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| Veröffentlicht in: | Molecular and cellular biology 2015-06, Vol.35 (11), p.1940-1951 |
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| container_title | Molecular and cellular biology |
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| creator | Liu, Yen-Nien Yin, JuanJuan Barrett, Ben Sheppard-Tillman, Heather Li, Dongmei Casey, Orla M. Fang, Lei Hynes, Paul G. Ameri, Amir H. Kelly, Kathleen |
| description | Bone metastasis is the hallmark of progressive and castration-resistant prostate cancers. MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that SRC is a direct target of miR-1. In prostate cancer patient samples, miR-1 levels are inversely correlated with SRC expression and a SRC-dependent gene signature. Ectopic miR-1 expression inhibited extracellular signal-regulated kinase (ERK) signaling and bone metastasis in a xenograft model. In contrast, SRC overexpression was sufficient to reconstitute bone metastasis and ERK signaling in cells expressing high levels of miR-1. Androgen receptor (AR) activity, defined by an AR output signature, is low in a portion of castration-resistant prostate cancer. We show that AR binds to the miR-1-2 regulatory region and regulates miR-1 transcription. Patients with low miR-1 levels displayed correlated low canonical AR gene signatures. Our data support the existence of an AR-miR-1-SRC regulatory network. We propose that loss of miR-1 is one mechanistic link between low canonical AR output and SRC-promoted metastatic phenotypes. |
| doi_str_mv | 10.1128/MCB.00008-15 |
| format | Article |
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MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that SRC is a direct target of miR-1. In prostate cancer patient samples, miR-1 levels are inversely correlated with SRC expression and a SRC-dependent gene signature. Ectopic miR-1 expression inhibited extracellular signal-regulated kinase (ERK) signaling and bone metastasis in a xenograft model. In contrast, SRC overexpression was sufficient to reconstitute bone metastasis and ERK signaling in cells expressing high levels of miR-1. Androgen receptor (AR) activity, defined by an AR output signature, is low in a portion of castration-resistant prostate cancer. We show that AR binds to the miR-1-2 regulatory region and regulates miR-1 transcription. Patients with low miR-1 levels displayed correlated low canonical AR gene signatures. Our data support the existence of an AR-miR-1-SRC regulatory network. We propose that loss of miR-1 is one mechanistic link between low canonical AR output and SRC-promoted metastatic phenotypes.</description><identifier>ISSN: 1098-5549</identifier><identifier>ISSN: 0270-7306</identifier><identifier>EISSN: 1098-5549</identifier><identifier>DOI: 10.1128/MCB.00008-15</identifier><identifier>PMID: 25802280</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>Androgens - genetics ; Animals ; Bone Neoplasms - genetics ; Bone Neoplasms - pathology ; Bone Neoplasms - secondary ; Cell Line, Tumor ; Extracellular Signal-Regulated MAP Kinases - genetics ; Gene Expression Regulation, Neoplastic - genetics ; Humans ; Male ; Mice ; Mice, Nude ; MicroRNAs - genetics ; Prostatic Neoplasms, Castration-Resistant - genetics ; Prostatic Neoplasms, Castration-Resistant - pathology ; Receptors, Androgen - genetics ; Signal Transduction - genetics ; src-Family Kinases - genetics</subject><ispartof>Molecular and cellular biology, 2015-06, Vol.35 (11), p.1940-1951</ispartof><rights>Copyright © 2015, American Society for Microbiology 2015</rights><rights>Copyright © 2015, American Society for Microbiology. All Rights Reserved.</rights><rights>Copyright © 2015, American Society for Microbiology. All Rights Reserved. 2015 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-33ad4ea0d43d596af119588a10b6051b2edcd9535ebc58d3030ae9f7e97322d93</citedby><cites>FETCH-LOGICAL-c508t-33ad4ea0d43d596af119588a10b6051b2edcd9535ebc58d3030ae9f7e97322d93</cites><orcidid>0000-0001-6739-5463</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420926/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420926/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25802280$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Yen-Nien</creatorcontrib><creatorcontrib>Yin, JuanJuan</creatorcontrib><creatorcontrib>Barrett, Ben</creatorcontrib><creatorcontrib>Sheppard-Tillman, Heather</creatorcontrib><creatorcontrib>Li, Dongmei</creatorcontrib><creatorcontrib>Casey, Orla M.</creatorcontrib><creatorcontrib>Fang, Lei</creatorcontrib><creatorcontrib>Hynes, Paul G.</creatorcontrib><creatorcontrib>Ameri, Amir H.</creatorcontrib><creatorcontrib>Kelly, Kathleen</creatorcontrib><title>Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis</title><title>Molecular and cellular biology</title><addtitle>Mol Cell Biol</addtitle><description>Bone metastasis is the hallmark of progressive and castration-resistant prostate cancers. MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that SRC is a direct target of miR-1. In prostate cancer patient samples, miR-1 levels are inversely correlated with SRC expression and a SRC-dependent gene signature. Ectopic miR-1 expression inhibited extracellular signal-regulated kinase (ERK) signaling and bone metastasis in a xenograft model. In contrast, SRC overexpression was sufficient to reconstitute bone metastasis and ERK signaling in cells expressing high levels of miR-1. Androgen receptor (AR) activity, defined by an AR output signature, is low in a portion of castration-resistant prostate cancer. We show that AR binds to the miR-1-2 regulatory region and regulates miR-1 transcription. Patients with low miR-1 levels displayed correlated low canonical AR gene signatures. Our data support the existence of an AR-miR-1-SRC regulatory network. We propose that loss of miR-1 is one mechanistic link between low canonical AR output and SRC-promoted metastatic phenotypes.</description><subject>Androgens - genetics</subject><subject>Animals</subject><subject>Bone Neoplasms - genetics</subject><subject>Bone Neoplasms - pathology</subject><subject>Bone Neoplasms - secondary</subject><subject>Cell Line, Tumor</subject><subject>Extracellular Signal-Regulated MAP Kinases - genetics</subject><subject>Gene Expression Regulation, Neoplastic - genetics</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>MicroRNAs - genetics</subject><subject>Prostatic Neoplasms, Castration-Resistant - genetics</subject><subject>Prostatic Neoplasms, Castration-Resistant - pathology</subject><subject>Receptors, Androgen - genetics</subject><subject>Signal Transduction - genetics</subject><subject>src-Family Kinases - genetics</subject><issn>1098-5549</issn><issn>0270-7306</issn><issn>1098-5549</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1P3DAQxS3Uiq9y6xn52AOh_ogT-1JpiSgg7dJqgbPrjSeLUWKDnaXiv6-3SxFISJ3LjN789DT2Q-gzJceUMvl11pwck1yyoGIL7VKiZCFEqT68mnfQXkp3GaoU4dtohwlJGJNkF_2ahpRw6PDE2xiW4Is5LFe9GcHimWtjmF9OMMWTdnSPWUz4at5g4y3-GcMQ1kIe0phXuDG-hYhPggc8g9FkNbn0CX3sTJ_g4Lnvo5vvp9fNeTH9cXbRTKZFK4gcC86NLcEQW3IrVGU6SpWQ0lCyqIigCwa2tUpwAYtWSMsJJwZUV4OqOWNW8X30beN7v1oMGQY_RtPr--gGE590ME6_3Xh3q5fhUZclI4pV2eDLs0EMDytIox5caqHvjYewSprWhJZ1TRn7P1pJQmXN-dr1aIPmr0wpQvdyESV6nZ_O-em_-WkqMn74-hUv8L_AMlBvAOe7EAfzO8Te6tE89SF2MSfgkubvWv8Bdv-nuA</recordid><startdate>20150601</startdate><enddate>20150601</enddate><creator>Liu, Yen-Nien</creator><creator>Yin, JuanJuan</creator><creator>Barrett, Ben</creator><creator>Sheppard-Tillman, Heather</creator><creator>Li, Dongmei</creator><creator>Casey, Orla M.</creator><creator>Fang, Lei</creator><creator>Hynes, Paul G.</creator><creator>Ameri, Amir H.</creator><creator>Kelly, Kathleen</creator><general>Taylor & Francis</general><general>American Society for Microbiology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7QP</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6739-5463</orcidid></search><sort><creationdate>20150601</creationdate><title>Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis</title><author>Liu, Yen-Nien ; Yin, JuanJuan ; Barrett, Ben ; Sheppard-Tillman, Heather ; Li, Dongmei ; Casey, Orla M. ; Fang, Lei ; Hynes, Paul G. ; Ameri, Amir H. ; Kelly, Kathleen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c508t-33ad4ea0d43d596af119588a10b6051b2edcd9535ebc58d3030ae9f7e97322d93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Androgens - genetics</topic><topic>Animals</topic><topic>Bone Neoplasms - genetics</topic><topic>Bone Neoplasms - pathology</topic><topic>Bone Neoplasms - secondary</topic><topic>Cell Line, Tumor</topic><topic>Extracellular Signal-Regulated MAP Kinases - genetics</topic><topic>Gene Expression Regulation, Neoplastic - genetics</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>MicroRNAs - genetics</topic><topic>Prostatic Neoplasms, Castration-Resistant - genetics</topic><topic>Prostatic Neoplasms, Castration-Resistant - pathology</topic><topic>Receptors, Androgen - genetics</topic><topic>Signal Transduction - genetics</topic><topic>src-Family Kinases - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Yen-Nien</creatorcontrib><creatorcontrib>Yin, JuanJuan</creatorcontrib><creatorcontrib>Barrett, Ben</creatorcontrib><creatorcontrib>Sheppard-Tillman, Heather</creatorcontrib><creatorcontrib>Li, Dongmei</creatorcontrib><creatorcontrib>Casey, Orla M.</creatorcontrib><creatorcontrib>Fang, Lei</creatorcontrib><creatorcontrib>Hynes, Paul G.</creatorcontrib><creatorcontrib>Ameri, Amir H.</creatorcontrib><creatorcontrib>Kelly, Kathleen</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular and cellular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Yen-Nien</au><au>Yin, JuanJuan</au><au>Barrett, Ben</au><au>Sheppard-Tillman, Heather</au><au>Li, Dongmei</au><au>Casey, Orla M.</au><au>Fang, Lei</au><au>Hynes, Paul G.</au><au>Ameri, Amir H.</au><au>Kelly, Kathleen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis</atitle><jtitle>Molecular and cellular biology</jtitle><addtitle>Mol Cell Biol</addtitle><date>2015-06-01</date><risdate>2015</risdate><volume>35</volume><issue>11</issue><spage>1940</spage><epage>1951</epage><pages>1940-1951</pages><issn>1098-5549</issn><issn>0270-7306</issn><eissn>1098-5549</eissn><abstract>Bone metastasis is the hallmark of progressive and castration-resistant prostate cancers. MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that SRC is a direct target of miR-1. In prostate cancer patient samples, miR-1 levels are inversely correlated with SRC expression and a SRC-dependent gene signature. Ectopic miR-1 expression inhibited extracellular signal-regulated kinase (ERK) signaling and bone metastasis in a xenograft model. In contrast, SRC overexpression was sufficient to reconstitute bone metastasis and ERK signaling in cells expressing high levels of miR-1. Androgen receptor (AR) activity, defined by an AR output signature, is low in a portion of castration-resistant prostate cancer. We show that AR binds to the miR-1-2 regulatory region and regulates miR-1 transcription. Patients with low miR-1 levels displayed correlated low canonical AR gene signatures. Our data support the existence of an AR-miR-1-SRC regulatory network. We propose that loss of miR-1 is one mechanistic link between low canonical AR output and SRC-promoted metastatic phenotypes.</abstract><cop>United States</cop><pub>Taylor & Francis</pub><pmid>25802280</pmid><doi>10.1128/MCB.00008-15</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-6739-5463</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Androgens - genetics Animals Bone Neoplasms - genetics Bone Neoplasms - pathology Bone Neoplasms - secondary Cell Line, Tumor Extracellular Signal-Regulated MAP Kinases - genetics Gene Expression Regulation, Neoplastic - genetics Humans Male Mice Mice, Nude MicroRNAs - genetics Prostatic Neoplasms, Castration-Resistant - genetics Prostatic Neoplasms, Castration-Resistant - pathology Receptors, Androgen - genetics Signal Transduction - genetics src-Family Kinases - genetics |
| title | Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis |
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