Lymphatic Reprogramming by Kaposi Sarcoma Herpes Virus Promotes the Oncogenic Activity of the Virus-Encoded G-protein Coupled Receptor
Identifieur interne : 004176 ( Main/Exploration ); précédent : 004175; suivant : 004177Lymphatic Reprogramming by Kaposi Sarcoma Herpes Virus Promotes the Oncogenic Activity of the Virus-Encoded G-protein Coupled Receptor
Auteurs : Berenice Aguilar [États-Unis] ; Inho Choi [États-Unis] ; Dongwon Choi [États-Unis] ; Hee Kyoung Chung [États-Unis] ; Sunju Lee [États-Unis] ; Jaehyuk Yoo [États-Unis] ; Yong Suk Lee [États-Unis] ; Yong Sun Maeng [États-Unis] ; Ha Neul Lee [États-Unis] ; Eunkyung Park [États-Unis] ; Kyu Eui Kim [États-Unis] ; Nam Yoon Kim [États-Unis] ; Jae Myung Baik [États-Unis] ; Jae U. Jung [États-Unis] ; Chester J. Koh [États-Unis] ; Young-Kwon Hong [États-Unis]Source :
- Cancer research [ 0008-5472 ] ; 2012.
Abstract
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.
Url:
DOI: 10.1158/0008-5472.CAN-12-1229
PubMed: 22942256
PubMed Central: 3500425
Affiliations:
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<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>
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<author><name sortKey="Baik, Jae Myung" sort="Baik, Jae Myung" uniqKey="Baik J" first="Jae Myung" last="Baik">Jae Myung Baik</name>
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<author><name sortKey="Jung, Jae U" sort="Jung, Jae U" uniqKey="Jung J" first="Jae U." last="Jung">Jae U. Jung</name>
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<country xml:lang="fr">États-Unis</country>
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</author>
<author><name sortKey="Hong, Young Kwon" sort="Hong, Young Kwon" uniqKey="Hong Y" first="Young-Kwon" last="Hong">Young-Kwon Hong</name>
<affiliation wicri:level="2"><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>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Californie</region>
</placeName>
<wicri:cityArea> Department of Surgery and Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles</wicri:cityArea>
</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>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Californie</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Californie"><name sortKey="Aguilar, Berenice" sort="Aguilar, Berenice" uniqKey="Aguilar B" first="Berenice" last="Aguilar">Berenice Aguilar</name>
</region>
<name sortKey="Baik, Jae Myung" sort="Baik, Jae Myung" uniqKey="Baik J" first="Jae Myung" last="Baik">Jae Myung Baik</name>
<name sortKey="Choi, Dongwon" sort="Choi, Dongwon" uniqKey="Choi D" first="Dongwon" last="Choi">Dongwon Choi</name>
<name sortKey="Choi, Inho" sort="Choi, Inho" uniqKey="Choi I" first="Inho" last="Choi">Inho Choi</name>
<name sortKey="Chung, Hee Kyoung" sort="Chung, Hee Kyoung" uniqKey="Chung H" first="Hee Kyoung" last="Chung">Hee Kyoung Chung</name>
<name sortKey="Hong, Young Kwon" sort="Hong, Young Kwon" uniqKey="Hong Y" first="Young-Kwon" last="Hong">Young-Kwon Hong</name>
<name sortKey="Jung, Jae U" sort="Jung, Jae U" uniqKey="Jung J" first="Jae U." last="Jung">Jae U. Jung</name>
<name sortKey="Kim, Kyu Eui" sort="Kim, Kyu Eui" uniqKey="Kim K" first="Kyu Eui" last="Kim">Kyu Eui Kim</name>
<name sortKey="Kim, Nam Yoon" sort="Kim, Nam Yoon" uniqKey="Kim N" first="Nam Yoon" last="Kim">Nam Yoon Kim</name>
<name sortKey="Koh, Chester J" sort="Koh, Chester J" uniqKey="Koh C" first="Chester J." last="Koh">Chester J. Koh</name>
<name sortKey="Lee, Ha Neul" sort="Lee, Ha Neul" uniqKey="Lee H" first="Ha Neul" last="Lee">Ha Neul Lee</name>
<name sortKey="Lee, Sunju" sort="Lee, Sunju" uniqKey="Lee S" first="Sunju" last="Lee">Sunju Lee</name>
<name sortKey="Lee, Yong Suk" sort="Lee, Yong Suk" uniqKey="Lee Y" first="Yong Suk" last="Lee">Yong Suk Lee</name>
<name sortKey="Maeng, Yong Sun" sort="Maeng, Yong Sun" uniqKey="Maeng Y" first="Yong Sun" last="Maeng">Yong Sun Maeng</name>
<name sortKey="Park, Eunkyung" sort="Park, Eunkyung" uniqKey="Park E" first="Eunkyung" last="Park">Eunkyung Park</name>
<name sortKey="Yoo, Jaehyuk" sort="Yoo, Jaehyuk" uniqKey="Yoo J" first="Jaehyuk" last="Yoo">Jaehyuk Yoo</name>
</country>
</tree>
</affiliations>
</record>
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