Metabolic characteristics of granulosa cell tumor: role of PPAR γ signaling
Granulosa cell tumors are relatively rare, posing challenges for comprehension and therapeutic development due to limited cases and preclinical models. Metabolic reprogramming, a hallmark of cancer, manifests in granulosa cell tumors with notable lipid accumulation and increased expression of peroxi...
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Veröffentlicht in: | Biology of reproduction 2024-03, Vol.110 (3), p.509-520 |
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description | Granulosa cell tumors are relatively rare, posing challenges for comprehension and therapeutic development due to limited cases and preclinical models. Metabolic reprogramming, a hallmark of cancer, manifests in granulosa cell tumors with notable lipid accumulation and increased expression of peroxisome proliferator–activated receptor gamma (PPARγ), a key lipid metabolism regulator. The roles of these features, however, remain unclear. In our previous work, we established a granulosa cell tumor model in mice by introducing a constitutively active Pik3ca mutant in oocytes, enabling the study of predictable tumor patterns from postnatal day 50. In this study, we characterized metabolic alterations during tumorigenesis (postnatal day 8 to day 50) and tumor growth (day 50 to day 65) in this model and explored the impact of PPARγ antagonism on human granulosa cell tumor proliferation. The tumor exhibited significant lipid accumulation, with PPARγ and the proliferation marker Ki67 co-localizing at postnatal day 65. Transcriptome analysis demonstrates that pathways for lipid metabolism and mitochondrial oxidation are promoted during tumorigenesis and tumor growth, respectively. Overlappingly upregulated genes during tumorigenesis and tumor growth are associated with lipid metabolism pathways. Correspondingly, mouse granulosa cell tumor shows overexpression of peroxisome proliferator–activated receptor gamma and DGAT2 proteins at postnatal day 65. Furthermore, GW9662 reduces the proliferation of KGN human granulosa cell tumor cells and decreases the phosphorylation of AKT and SMAD3. Our findings identify metabolic abnormalities in ooPIK3CA* granulosa cell tumor model and suggest peroxisome proliferator–activated receptor gamma as a potential driver for primary granulosa cell tumor growth. Summary Sentence Lipid accumulation and expression of PPAR gamma, a well-known lipogenic transcription factor, are promoted during mouse GCT development, and PPAR gamma inhibitor suppresses human GCT cell proliferation. Graphical Abstract |
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Metabolic reprogramming, a hallmark of cancer, manifests in granulosa cell tumors with notable lipid accumulation and increased expression of peroxisome proliferator–activated receptor gamma (PPARγ), a key lipid metabolism regulator. The roles of these features, however, remain unclear. In our previous work, we established a granulosa cell tumor model in mice by introducing a constitutively active Pik3ca mutant in oocytes, enabling the study of predictable tumor patterns from postnatal day 50. In this study, we characterized metabolic alterations during tumorigenesis (postnatal day 8 to day 50) and tumor growth (day 50 to day 65) in this model and explored the impact of PPARγ antagonism on human granulosa cell tumor proliferation. The tumor exhibited significant lipid accumulation, with PPARγ and the proliferation marker Ki67 co-localizing at postnatal day 65. Transcriptome analysis demonstrates that pathways for lipid metabolism and mitochondrial oxidation are promoted during tumorigenesis and tumor growth, respectively. Overlappingly upregulated genes during tumorigenesis and tumor growth are associated with lipid metabolism pathways. Correspondingly, mouse granulosa cell tumor shows overexpression of peroxisome proliferator–activated receptor gamma and DGAT2 proteins at postnatal day 65. Furthermore, GW9662 reduces the proliferation of KGN human granulosa cell tumor cells and decreases the phosphorylation of AKT and SMAD3. Our findings identify metabolic abnormalities in ooPIK3CA* granulosa cell tumor model and suggest peroxisome proliferator–activated receptor gamma as a potential driver for primary granulosa cell tumor growth. Summary Sentence Lipid accumulation and expression of PPAR gamma, a well-known lipogenic transcription factor, are promoted during mouse GCT development, and PPAR gamma inhibitor suppresses human GCT cell proliferation. Graphical Abstract</description><identifier>ISSN: 0006-3363</identifier><identifier>EISSN: 1529-7268</identifier><identifier>DOI: 10.1093/biolre/ioad173</identifier><identifier>PMID: 38123510</identifier><language>eng</language><publisher>United States: Society for the Study of Reproduction</publisher><subject>AKT protein ; Cell culture ; Cell proliferation ; granulosa cell tumor ; Lipid metabolism ; Lipids ; Metabolism ; oocyte-specific Pik3ca knock-in ; Oocytes ; Peroxisome proliferator-activated receptors ; peroxisome proliferator–activated receptor gamma ; Phosphorylation ; Postpartum period ; RESEARCH ARTICLE ; Smad3 protein ; Transcriptomes ; Tumor cells ; Tumorigenesis ; Tumors</subject><ispartof>Biology of reproduction, 2024-03, Vol.110 (3), p.509-520</ispartof><rights>The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com 2024</rights><rights>The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.</rights><rights>The Author(s) 2023. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-b405t-f6d22fa161f4037ecf6a00ce5eedf67f1f308bb4ebeb653fee16d2d20dadea833</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,1584,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38123510$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yu, Seok-Yeong</creatorcontrib><creatorcontrib>Luan, Yi</creatorcontrib><creatorcontrib>Xu, Pauline C.</creatorcontrib><creatorcontrib>Zhang, Yaqi</creatorcontrib><creatorcontrib>Dong, Rosemary</creatorcontrib><creatorcontrib>Abazarikia, Amirhossein</creatorcontrib><creatorcontrib>Kim, So-Youn</creatorcontrib><title>Metabolic characteristics of granulosa cell tumor: role of PPAR γ signaling</title><title>Biology of reproduction</title><addtitle>Biol Reprod</addtitle><description>Granulosa cell tumors are relatively rare, posing challenges for comprehension and therapeutic development due to limited cases and preclinical models. Metabolic reprogramming, a hallmark of cancer, manifests in granulosa cell tumors with notable lipid accumulation and increased expression of peroxisome proliferator–activated receptor gamma (PPARγ), a key lipid metabolism regulator. The roles of these features, however, remain unclear. In our previous work, we established a granulosa cell tumor model in mice by introducing a constitutively active Pik3ca mutant in oocytes, enabling the study of predictable tumor patterns from postnatal day 50. In this study, we characterized metabolic alterations during tumorigenesis (postnatal day 8 to day 50) and tumor growth (day 50 to day 65) in this model and explored the impact of PPARγ antagonism on human granulosa cell tumor proliferation. The tumor exhibited significant lipid accumulation, with PPARγ and the proliferation marker Ki67 co-localizing at postnatal day 65. Transcriptome analysis demonstrates that pathways for lipid metabolism and mitochondrial oxidation are promoted during tumorigenesis and tumor growth, respectively. Overlappingly upregulated genes during tumorigenesis and tumor growth are associated with lipid metabolism pathways. Correspondingly, mouse granulosa cell tumor shows overexpression of peroxisome proliferator–activated receptor gamma and DGAT2 proteins at postnatal day 65. Furthermore, GW9662 reduces the proliferation of KGN human granulosa cell tumor cells and decreases the phosphorylation of AKT and SMAD3. Our findings identify metabolic abnormalities in ooPIK3CA* granulosa cell tumor model and suggest peroxisome proliferator–activated receptor gamma as a potential driver for primary granulosa cell tumor growth. Summary Sentence Lipid accumulation and expression of PPAR gamma, a well-known lipogenic transcription factor, are promoted during mouse GCT development, and PPAR gamma inhibitor suppresses human GCT cell proliferation. Graphical Abstract</description><subject>AKT protein</subject><subject>Cell culture</subject><subject>Cell proliferation</subject><subject>granulosa cell tumor</subject><subject>Lipid metabolism</subject><subject>Lipids</subject><subject>Metabolism</subject><subject>oocyte-specific Pik3ca knock-in</subject><subject>Oocytes</subject><subject>Peroxisome proliferator-activated receptors</subject><subject>peroxisome proliferator–activated receptor gamma</subject><subject>Phosphorylation</subject><subject>Postpartum period</subject><subject>RESEARCH ARTICLE</subject><subject>Smad3 protein</subject><subject>Transcriptomes</subject><subject>Tumor cells</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><issn>0006-3363</issn><issn>1529-7268</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNqFkcFO3DAQhi1UVLa0V44oUi-tRGDsSZxsLxVCLUVaVITo2XKc8WLkjRc7qcRz8R59pmaVLSpcOI3k-eaf-f0zdsDhmMMcTxoXfKQTF3TLK9xhM16KeV4JWb9hMwCQOaLEPfYupTsAXqDAt2wPay6w5DBji0vqdRO8M5m51VGbnqJLvTMpCzZbRt0NPiSdGfI-64dViF-yGDxtuldXp9fZn8csuWWnveuW79mu1T7Rh23dZ7--f7s5-5Evfp5fnJ0u8qaAss-tbIWwmktuC8CKjJUawFBJ1FpZWW4R6qYpqKFGlmiJ-DjRCmh1S7pG3GdfJ9310KyoNdT1UXu1jm6l44MK2qnnnc7dqmX4rcYvKzjUclT4tFWI4X6g1KuVSxuPuqMwJCXmUJSyquZ8RD--QO_CEEfDSSEXNQAWxYY6nigTQ0qR7NM1HDZrUU1JqW1S48Dh_x6e8H_RjMDnCQjD-nWxo4kd30NHr-F_AS6usRo</recordid><startdate>20240313</startdate><enddate>20240313</enddate><creator>Yu, Seok-Yeong</creator><creator>Luan, Yi</creator><creator>Xu, Pauline C.</creator><creator>Zhang, Yaqi</creator><creator>Dong, Rosemary</creator><creator>Abazarikia, Amirhossein</creator><creator>Kim, So-Youn</creator><general>Society for the Study of Reproduction</general><general>Oxford University Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20240313</creationdate><title>Metabolic characteristics of granulosa cell tumor: role of PPAR γ signaling</title><author>Yu, Seok-Yeong ; Luan, Yi ; Xu, Pauline C. ; Zhang, Yaqi ; Dong, Rosemary ; Abazarikia, Amirhossein ; Kim, So-Youn</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b405t-f6d22fa161f4037ecf6a00ce5eedf67f1f308bb4ebeb653fee16d2d20dadea833</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>AKT protein</topic><topic>Cell culture</topic><topic>Cell proliferation</topic><topic>granulosa cell tumor</topic><topic>Lipid metabolism</topic><topic>Lipids</topic><topic>Metabolism</topic><topic>oocyte-specific Pik3ca knock-in</topic><topic>Oocytes</topic><topic>Peroxisome proliferator-activated receptors</topic><topic>peroxisome proliferator–activated receptor gamma</topic><topic>Phosphorylation</topic><topic>Postpartum period</topic><topic>RESEARCH ARTICLE</topic><topic>Smad3 protein</topic><topic>Transcriptomes</topic><topic>Tumor cells</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yu, Seok-Yeong</creatorcontrib><creatorcontrib>Luan, Yi</creatorcontrib><creatorcontrib>Xu, Pauline C.</creatorcontrib><creatorcontrib>Zhang, Yaqi</creatorcontrib><creatorcontrib>Dong, Rosemary</creatorcontrib><creatorcontrib>Abazarikia, Amirhossein</creatorcontrib><creatorcontrib>Kim, So-Youn</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biology of reproduction</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yu, Seok-Yeong</au><au>Luan, Yi</au><au>Xu, Pauline C.</au><au>Zhang, Yaqi</au><au>Dong, Rosemary</au><au>Abazarikia, Amirhossein</au><au>Kim, So-Youn</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Metabolic characteristics of granulosa cell tumor: role of PPAR γ signaling</atitle><jtitle>Biology of reproduction</jtitle><addtitle>Biol Reprod</addtitle><date>2024-03-13</date><risdate>2024</risdate><volume>110</volume><issue>3</issue><spage>509</spage><epage>520</epage><pages>509-520</pages><issn>0006-3363</issn><eissn>1529-7268</eissn><abstract>Granulosa cell tumors are relatively rare, posing challenges for comprehension and therapeutic development due to limited cases and preclinical models. Metabolic reprogramming, a hallmark of cancer, manifests in granulosa cell tumors with notable lipid accumulation and increased expression of peroxisome proliferator–activated receptor gamma (PPARγ), a key lipid metabolism regulator. The roles of these features, however, remain unclear. In our previous work, we established a granulosa cell tumor model in mice by introducing a constitutively active Pik3ca mutant in oocytes, enabling the study of predictable tumor patterns from postnatal day 50. In this study, we characterized metabolic alterations during tumorigenesis (postnatal day 8 to day 50) and tumor growth (day 50 to day 65) in this model and explored the impact of PPARγ antagonism on human granulosa cell tumor proliferation. The tumor exhibited significant lipid accumulation, with PPARγ and the proliferation marker Ki67 co-localizing at postnatal day 65. Transcriptome analysis demonstrates that pathways for lipid metabolism and mitochondrial oxidation are promoted during tumorigenesis and tumor growth, respectively. Overlappingly upregulated genes during tumorigenesis and tumor growth are associated with lipid metabolism pathways. Correspondingly, mouse granulosa cell tumor shows overexpression of peroxisome proliferator–activated receptor gamma and DGAT2 proteins at postnatal day 65. Furthermore, GW9662 reduces the proliferation of KGN human granulosa cell tumor cells and decreases the phosphorylation of AKT and SMAD3. Our findings identify metabolic abnormalities in ooPIK3CA* granulosa cell tumor model and suggest peroxisome proliferator–activated receptor gamma as a potential driver for primary granulosa cell tumor growth. Summary Sentence Lipid accumulation and expression of PPAR gamma, a well-known lipogenic transcription factor, are promoted during mouse GCT development, and PPAR gamma inhibitor suppresses human GCT cell proliferation. Graphical Abstract</abstract><cop>United States</cop><pub>Society for the Study of Reproduction</pub><pmid>38123510</pmid><doi>10.1093/biolre/ioad173</doi><tpages>12</tpages></addata></record> |
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subjects | AKT protein Cell culture Cell proliferation granulosa cell tumor Lipid metabolism Lipids Metabolism oocyte-specific Pik3ca knock-in Oocytes Peroxisome proliferator-activated receptors peroxisome proliferator–activated receptor gamma Phosphorylation Postpartum period RESEARCH ARTICLE Smad3 protein Transcriptomes Tumor cells Tumorigenesis Tumors |
title | Metabolic characteristics of granulosa cell tumor: role of PPAR γ signaling |
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