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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Lymphatic Reprogramming by Kaposi Sarcoma Herpes Virus Promotes the Oncogenic Activity of the Virus-Encoded G-protein Coupled Receptor</title><author><name sortKey="Aguilar, Berenice" sort="Aguilar, Berenice" uniqKey="Aguilar B" first="Berenice" last="Aguilar">Berenice Aguilar</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Choi, Inho" sort="Choi, Inho" uniqKey="Choi I" first="Inho" last="Choi">Inho Choi</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Choi, Dongwon" sort="Choi, Dongwon" uniqKey="Choi D" first="Dongwon" last="Choi">Dongwon Choi</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Chung, Hee Kyoung" sort="Chung, Hee Kyoung" uniqKey="Chung H" first="Hee Kyoung" last="Chung">Hee Kyoung Chung</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Lee, Sunju" sort="Lee, Sunju" uniqKey="Lee S" first="Sunju" last="Lee">Sunju Lee</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Yoo, Jaehyuk" sort="Yoo, Jaehyuk" uniqKey="Yoo J" first="Jaehyuk" last="Yoo">Jaehyuk Yoo</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Lee, Yong Suk" sort="Lee, Yong Suk" uniqKey="Lee Y" first="Yong Suk" last="Lee">Yong Suk Lee</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Maeng, Yong Sun" sort="Maeng, Yong Sun" uniqKey="Maeng Y" first="Yong Sun" last="Maeng">Yong Sun Maeng</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Lee, Ha Neul" sort="Lee, Ha Neul" uniqKey="Lee H" first="Ha Neul" last="Lee">Ha Neul Lee</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Park, Eunkyung" sort="Park, Eunkyung" uniqKey="Park E" first="Eunkyung" last="Park">Eunkyung Park</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Kim, Kyu Eui" sort="Kim, Kyu Eui" uniqKey="Kim K" first="Kyu Eui" last="Kim">Kyu Eui Kim</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Kim, Nam Yoon" sort="Kim, Nam Yoon" uniqKey="Kim N" first="Nam Yoon" last="Kim">Nam Yoon Kim</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Baik, Jae Myung" sort="Baik, Jae Myung" uniqKey="Baik J" first="Jae Myung" last="Baik">Jae Myung Baik</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Jung, Jae U" sort="Jung, Jae U" uniqKey="Jung J" first="Jae U." last="Jung">Jae U. Jung</name><affiliation><nlm:aff id="A2">Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Koh, Chester J" sort="Koh, Chester J" uniqKey="Koh C" first="Chester J." last="Koh">Chester J. Koh</name><affiliation><nlm:aff id="A3">Division of Pediatric Urology and Developmental Biology, Regenerative Medicine, and Surgery Program, Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California 90027</nlm:aff></affiliation></author><author><name sortKey="Hong, Young Kwon" sort="Hong, Young Kwon" uniqKey="Hong Y" first="Young-Kwon" last="Hong">Young-Kwon Hong</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22942256</idno><idno type="pmc">3500425</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500425</idno><idno type="RBID">PMC:3500425</idno><idno type="doi">10.1158/0008-5472.CAN-12-1229</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">003652</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">003652</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Lymphatic Reprogramming by Kaposi Sarcoma Herpes Virus Promotes the Oncogenic Activity of the Virus-Encoded G-protein Coupled Receptor</title><author><name sortKey="Aguilar, Berenice" sort="Aguilar, Berenice" uniqKey="Aguilar B" first="Berenice" last="Aguilar">Berenice Aguilar</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Choi, Inho" sort="Choi, Inho" uniqKey="Choi I" first="Inho" last="Choi">Inho Choi</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Choi, Dongwon" sort="Choi, Dongwon" uniqKey="Choi D" first="Dongwon" last="Choi">Dongwon Choi</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Chung, Hee Kyoung" sort="Chung, Hee Kyoung" uniqKey="Chung H" first="Hee Kyoung" last="Chung">Hee Kyoung Chung</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Lee, Sunju" sort="Lee, Sunju" uniqKey="Lee S" first="Sunju" last="Lee">Sunju Lee</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Yoo, Jaehyuk" sort="Yoo, Jaehyuk" uniqKey="Yoo J" first="Jaehyuk" last="Yoo">Jaehyuk Yoo</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Lee, Yong Suk" sort="Lee, Yong Suk" uniqKey="Lee Y" first="Yong Suk" last="Lee">Yong Suk Lee</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Maeng, Yong Sun" sort="Maeng, Yong Sun" uniqKey="Maeng Y" first="Yong Sun" last="Maeng">Yong Sun Maeng</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Lee, Ha Neul" sort="Lee, Ha Neul" uniqKey="Lee H" first="Ha Neul" last="Lee">Ha Neul Lee</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Park, Eunkyung" sort="Park, Eunkyung" uniqKey="Park E" first="Eunkyung" last="Park">Eunkyung Park</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Kim, Kyu Eui" sort="Kim, Kyu Eui" uniqKey="Kim K" first="Kyu Eui" last="Kim">Kyu Eui Kim</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Kim, Nam Yoon" sort="Kim, Nam Yoon" uniqKey="Kim N" first="Nam Yoon" last="Kim">Nam Yoon Kim</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Baik, Jae Myung" sort="Baik, Jae Myung" uniqKey="Baik J" first="Jae Myung" last="Baik">Jae Myung Baik</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Jung, Jae U" sort="Jung, Jae U" uniqKey="Jung J" first="Jae U." last="Jung">Jae U. Jung</name><affiliation><nlm:aff id="A2">Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author><author><name sortKey="Koh, Chester J" sort="Koh, Chester J" uniqKey="Koh C" first="Chester J." last="Koh">Chester J. Koh</name><affiliation><nlm:aff id="A3">Division of Pediatric Urology and Developmental Biology, Regenerative Medicine, and Surgery Program, Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California 90027</nlm:aff></affiliation></author><author><name sortKey="Hong, Young Kwon" sort="Hong, Young Kwon" uniqKey="Hong Y" first="Young-Kwon" last="Hong">Young-Kwon Hong</name><affiliation><nlm:aff id="A1"> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</nlm:aff></affiliation></author></analytic><series><title level="j">Cancer research</title><idno type="ISSN">0008-5472</idno><idno type="eISSN">1538-7445</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P2">Kaposi sarcoma (KS), the most common cancer in HIV-positive individuals, is caused by endothelial transformation mediated by the KS herpes virus (KSHV)-encoded G-protein coupled receptor (vGPCR). Infection of blood vascular endothelial cells (BECs) by KSHV reactivates an otherwise silenced embryonic program of lymphatic differentiation. Thus, KS tumors express numerous lymphatic endothelial cell (LEC)-signature genes. A key unanswered question is how lymphatic reprogramming by the virus promotes tumorigenesis leading to KS formation. In this study, we present evidence that this process creates an environment needed to license the oncogenic activity of vGPCR. We found that the G-protein regulator RGS4 is an inhibitor of vGPCR that is expressed in BECs, but not in LECs. RGS4 was downregulated by the master regulator of LEC differentiation PROX1, which is upregulated by KSHV and directs KSHV-induced lymphatic reprogramming. Moreover, we found that KSHV upregulates the nuclear receptor LRH1, which physically interacts with PROX1 and synergizes with it to mediate repression of RGS4 expression. Mechanistic investigations revealed that RGS4 reduced vGPCR-enhanced cell proliferation, migration, VEGF expression and Akt activation and to suppress tumor formation induced by vGPCR. Our findings resolve long-standing questions about the pathological impact of KSHV-induced reprogramming of host cell identity, and they offer biological and mechanistic insights supporting the hypothesis that a lymphatic microenvironment is more favorable for KS tumorigenesis.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">2984705R</journal-id><journal-id journal-id-type="pubmed-jr-id">2786</journal-id><journal-id journal-id-type="nlm-ta">Cancer Res</journal-id><journal-id journal-id-type="iso-abbrev">Cancer Res.</journal-id><journal-title-group><journal-title>Cancer research</journal-title></journal-title-group><issn pub-type="ppub">0008-5472</issn><issn pub-type="epub">1538-7445</issn></journal-meta><article-meta><article-id pub-id-type="pmid">22942256</article-id><article-id pub-id-type="pmc">3500425</article-id><article-id pub-id-type="doi">10.1158/0008-5472.CAN-12-1229</article-id><article-id pub-id-type="manuscript">NIHMS404933</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Lymphatic Reprogramming by Kaposi Sarcoma Herpes Virus Promotes the Oncogenic Activity of the Virus-Encoded G-protein Coupled Receptor</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Aguilar</surname><given-names>Berenice</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FN1">4</xref></contrib><contrib contrib-type="author"><name><surname>Choi</surname><given-names>Inho</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FN1">4</xref></contrib><contrib contrib-type="author"><name><surname>Choi</surname><given-names>Dongwon</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chung</surname><given-names>Hee Kyoung</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Sunju</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Yoo</surname><given-names>Jaehyuk</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Yong Suk</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Maeng</surname><given-names>Yong Sun</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Ha Neul</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Eunkyung</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Kyu Eui</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Nam Yoon</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Baik</surname><given-names>Jae Myung</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Jung</surname><given-names>Jae U.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Koh</surname><given-names>Chester J.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Hong</surname><given-names>Young-Kwon</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib></contrib-group><aff id="A1"><label>1</label> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</aff><aff id="A2"><label>2</label>Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033</aff><aff id="A3"><label>3</label>Division of Pediatric Urology and Developmental Biology, Regenerative Medicine, and Surgery Program, Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California 90027</aff><author-notes><corresp id="cor1">Correspondence should be addressed to: Young-Kwon Hong, Ph. D. Departments of Surgery and of Biochemistry and Molecular Biology University of Southern California Norris Comprehensive Cancer Center 1450 Biggy St. NRT6501, Mail Code 9601 Los Angeles, CA 90033 Tel: 323-442-7825, FAX: 323-442-7844, <email>young.hong@usc.edu</email></corresp><fn id="FN1" fn-type="equal"><label>4</label><p id="P1">These authors equally contributed to this work.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>4</day><month>9</month><year>2012</year></pub-date><pub-date pub-type="epub"><day>31</day><month>8</month><year>2012</year></pub-date><pub-date pub-type="ppub"><day>15</day><month>11</month><year>2012</year></pub-date><pub-date pub-type="pmc-release"><day>15</day><month>11</month><year>2013</year></pub-date><volume>72</volume><issue>22</issue><fpage>5833</fpage><lpage>5842</lpage><abstract><p id="P2">Kaposi sarcoma (KS), the most common cancer in HIV-positive individuals, is caused by endothelial transformation mediated by the KS herpes virus (KSHV)-encoded G-protein coupled receptor (vGPCR). Infection of blood vascular endothelial cells (BECs) by KSHV reactivates an otherwise silenced embryonic program of lymphatic differentiation. Thus, KS tumors express numerous lymphatic endothelial cell (LEC)-signature genes. A key unanswered question is how lymphatic reprogramming by the virus promotes tumorigenesis leading to KS formation. In this study, we present evidence that this process creates an environment needed to license the oncogenic activity of vGPCR. We found that the G-protein regulator RGS4 is an inhibitor of vGPCR that is expressed in BECs, but not in LECs. RGS4 was downregulated by the master regulator of LEC differentiation PROX1, which is upregulated by KSHV and directs KSHV-induced lymphatic reprogramming. Moreover, we found that KSHV upregulates the nuclear receptor LRH1, which physically interacts with PROX1 and synergizes with it to mediate repression of RGS4 expression. Mechanistic investigations revealed that RGS4 reduced vGPCR-enhanced cell proliferation, migration, VEGF expression and Akt activation and to suppress tumor formation induced by vGPCR. Our findings resolve long-standing questions about the pathological impact of KSHV-induced reprogramming of host cell identity, and they offer biological and mechanistic insights supporting the hypothesis that a lymphatic microenvironment is more favorable for KS tumorigenesis.</p></abstract><kwd-group><kwd>Kaposi sarcoma</kwd><kwd>lymphatic reprogramming</kwd><kwd>RGS4</kwd><kwd>viral GPCR</kwd><kwd>endothelial cells</kwd></kwd-group><funding-group><award-group><funding-source country="United States">National Institute of Child Health & Human Development : NICHD</funding-source><award-id>R01 HD059762 || HD</award-id></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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