VHL mutation drives human clear cell renal cell carcinoma progression through PI3K/AKT-dependent cholesteryl ester accumulation
Cholesteryl ester (CE) accumulation in intracellular lipid droplets (LDs) is an essential signature of clear cell renal cell carcinoma (ccRCC), but its molecular mechanism and pathological significance remain elusive. Enabled by the label-free Raman spectromicroscopy, which integrated stimulated Ram...
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| creator | Zhang, Shuo Fang, Tinghe He, Yexuan Feng, Weichen Yu, Zhuoyang Zheng, Yaoyao Zhang, Chi Hu, Shuai Liu, Zhuojun Liu, Jia Yu, Jian Zhang, Han He, Anbang Gong, Yanqing He, Zhisong Yang, Kaiwei Xi, Zhijun Yu, Wei Zhou, Liqun Yao, Lin Yue, Shuhua |
| description | Cholesteryl ester (CE) accumulation in intracellular lipid droplets (LDs) is an essential signature of clear cell renal cell carcinoma (ccRCC), but its molecular mechanism and pathological significance remain elusive.
Enabled by the label-free Raman spectromicroscopy, which integrated stimulated Raman scattering microscopy with confocal Raman spectroscopy on the same platform, we quantitatively analyzed LD distribution and composition at the single cell level in intact ccRCC cell and tissue specimens in situ without any processing or exogenous labeling. Since we found that commonly used ccRCC cell lines actually did not show the CE-rich signature, primary cancer cells were isolated from human tissues to retain the lipid signature of ccRCC with CE level as high as the original tissue, which offers a preferable cell model for the study of cholesterol metabolism in ccRCC. Moreover, we established a patient-derived xenograft (PDX) mouse model that retained the CE-rich phenotype of human ccRCC.
Surprisingly, our results revealed that CE accumulation was induced by tumor suppressor VHL mutation, the most common mutation of ccRCC. Moreover, VHL mutation was found to promote CE accumulation by upregulating HIFα and subsequent PI3K/AKT/mTOR/SREBPs pathway. Inspiringly, inhibition of cholesterol esterification remarkably suppressed ccRCC aggressiveness in vitro and in vivo with negligible toxicity, through the reduced membrane cholesterol-mediated downregulations of integrin and MAPK signaling pathways.
Collectively, our study improves current understanding of the role of CE accumulation in ccRCC and opens up new opportunities for treatment.
This work was supported by National Natural Science Foundation of China (No. U23B2046 and No. 62027824), National Key R&D Program of China (No. 2023YFC2415500), Fundamental Research Funds for the Central Universities (No. YWF-22-L-547), PKU-Baidu Fund (No. 2020BD033), Peking University First Hospital Scientific and Technological Achievement Transformation Incubation Guidance Fund (No. 2022CX02), and Beijing Municipal Health Commission (No. 2020-2Z-40713). |
| doi_str_mv | 10.1016/j.ebiom.2024.105070 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10999658</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S2352396424001051</els_id><sourcerecordid>3031662361</sourcerecordid><originalsourceid>FETCH-LOGICAL-c460t-c4826345a06344158dc9ac0b4a3acf6f1c45299fd8282a27d5eab023ec1ca4753</originalsourceid><addsrcrecordid>eNp9UU1v2zAMNYYNa9H1FwwYdNwlqb5jH4ahKLq1aIDt0O0qMDSdKLCtTLID9LS_PiVui_ayC0lQj-9RfEXxUfC54MJebOe08qGbSy517hi-4G-KU6mMnKnK6rcv6pPiPKUt51wYnZvl--JElcbqUi5Oi7-_b5asGwcYfOhZHf2eEtuMHfQMW4LIkNqWReqhnUqEiL4PHbBdDOtIKR0Gh00M43rDft6qu4vLu_tZTTvqa-oHhpvQUhooPrTsmBkgjt3YHiU_FO8aaBOdP-az4te36_urm9nyx_fbq8vlDLXlQ46ltEob4DlqYcoaK0C-0qAAG9sI1EZWVVOXspQgF7UhWHGpCAWCXhh1VnydeHfjqqMa82YRWreLvoP44AJ49_ql9xu3DnsneFVV1pSZ4fMjQwx_xvwT1_l0OAn0FMbkFFfCWqmsyFA1QTGGlCI1zzqCu4N9buuO9rmDfW6yL099erni88yTWRnwZQJQPtTeU3QJPfVItY-Eg6uD_6_APxdnrzw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3031662361</pqid></control><display><type>article</type><title>VHL mutation drives human clear cell renal cell carcinoma progression through PI3K/AKT-dependent cholesteryl ester accumulation</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Zhang, Shuo ; Fang, Tinghe ; He, Yexuan ; Feng, Weichen ; Yu, Zhuoyang ; Zheng, Yaoyao ; Zhang, Chi ; Hu, Shuai ; Liu, Zhuojun ; Liu, Jia ; Yu, Jian ; Zhang, Han ; He, Anbang ; Gong, Yanqing ; He, Zhisong ; Yang, Kaiwei ; Xi, Zhijun ; Yu, Wei ; Zhou, Liqun ; Yao, Lin ; Yue, Shuhua</creator><creatorcontrib>Zhang, Shuo ; Fang, Tinghe ; He, Yexuan ; Feng, Weichen ; Yu, Zhuoyang ; Zheng, Yaoyao ; Zhang, Chi ; Hu, Shuai ; Liu, Zhuojun ; Liu, Jia ; Yu, Jian ; Zhang, Han ; He, Anbang ; Gong, Yanqing ; He, Zhisong ; Yang, Kaiwei ; Xi, Zhijun ; Yu, Wei ; Zhou, Liqun ; Yao, Lin ; Yue, Shuhua</creatorcontrib><description>Cholesteryl ester (CE) accumulation in intracellular lipid droplets (LDs) is an essential signature of clear cell renal cell carcinoma (ccRCC), but its molecular mechanism and pathological significance remain elusive.
Enabled by the label-free Raman spectromicroscopy, which integrated stimulated Raman scattering microscopy with confocal Raman spectroscopy on the same platform, we quantitatively analyzed LD distribution and composition at the single cell level in intact ccRCC cell and tissue specimens in situ without any processing or exogenous labeling. Since we found that commonly used ccRCC cell lines actually did not show the CE-rich signature, primary cancer cells were isolated from human tissues to retain the lipid signature of ccRCC with CE level as high as the original tissue, which offers a preferable cell model for the study of cholesterol metabolism in ccRCC. Moreover, we established a patient-derived xenograft (PDX) mouse model that retained the CE-rich phenotype of human ccRCC.
Surprisingly, our results revealed that CE accumulation was induced by tumor suppressor VHL mutation, the most common mutation of ccRCC. Moreover, VHL mutation was found to promote CE accumulation by upregulating HIFα and subsequent PI3K/AKT/mTOR/SREBPs pathway. Inspiringly, inhibition of cholesterol esterification remarkably suppressed ccRCC aggressiveness in vitro and in vivo with negligible toxicity, through the reduced membrane cholesterol-mediated downregulations of integrin and MAPK signaling pathways.
Collectively, our study improves current understanding of the role of CE accumulation in ccRCC and opens up new opportunities for treatment.
This work was supported by National Natural Science Foundation of China (No. U23B2046 and No. 62027824), National Key R&D Program of China (No. 2023YFC2415500), Fundamental Research Funds for the Central Universities (No. YWF-22-L-547), PKU-Baidu Fund (No. 2020BD033), Peking University First Hospital Scientific and Technological Achievement Transformation Incubation Guidance Fund (No. 2022CX02), and Beijing Municipal Health Commission (No. 2020-2Z-40713).</description><identifier>ISSN: 2352-3964</identifier><identifier>EISSN: 2352-3964</identifier><identifier>DOI: 10.1016/j.ebiom.2024.105070</identifier><identifier>PMID: 38564827</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Animals ; Carcinoma, Renal Cell - genetics ; Carcinoma, Renal Cell - metabolism ; Carcinoma, Renal Cell - pathology ; Cell Line, Tumor ; Cholesterol Esters - metabolism ; Cholesterol metabolism ; Clear cell renal cell carcinoma ; Disease Models, Animal ; Disease Progression ; Humans ; Kidney Neoplasms - genetics ; Kidney Neoplasms - metabolism ; Kidney Neoplasms - pathology ; Mice ; Mutation ; Phosphatidylinositol 3-Kinases - metabolism ; Proto-Oncogene Proteins c-akt - metabolism ; Raman spectromicroscopy ; Signal Transduction ; Stimulated Raman scattering microscopy ; VHL mutation ; Von Hippel-Lindau Tumor Suppressor Protein - genetics ; Von Hippel-Lindau Tumor Suppressor Protein - metabolism</subject><ispartof>EBioMedicine, 2024-05, Vol.103, p.105070, Article 105070</ispartof><rights>2024 The Author(s)</rights><rights>Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.</rights><rights>2024 The Author(s) 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c460t-c4826345a06344158dc9ac0b4a3acf6f1c45299fd8282a27d5eab023ec1ca4753</citedby><cites>FETCH-LOGICAL-c460t-c4826345a06344158dc9ac0b4a3acf6f1c45299fd8282a27d5eab023ec1ca4753</cites><orcidid>0000-0003-3889-3329 ; 0000-0003-1830-008X</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/PMC10999658/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10999658/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,27928,27929,53795,53797</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38564827$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Shuo</creatorcontrib><creatorcontrib>Fang, Tinghe</creatorcontrib><creatorcontrib>He, Yexuan</creatorcontrib><creatorcontrib>Feng, Weichen</creatorcontrib><creatorcontrib>Yu, Zhuoyang</creatorcontrib><creatorcontrib>Zheng, Yaoyao</creatorcontrib><creatorcontrib>Zhang, Chi</creatorcontrib><creatorcontrib>Hu, Shuai</creatorcontrib><creatorcontrib>Liu, Zhuojun</creatorcontrib><creatorcontrib>Liu, Jia</creatorcontrib><creatorcontrib>Yu, Jian</creatorcontrib><creatorcontrib>Zhang, Han</creatorcontrib><creatorcontrib>He, Anbang</creatorcontrib><creatorcontrib>Gong, Yanqing</creatorcontrib><creatorcontrib>He, Zhisong</creatorcontrib><creatorcontrib>Yang, Kaiwei</creatorcontrib><creatorcontrib>Xi, Zhijun</creatorcontrib><creatorcontrib>Yu, Wei</creatorcontrib><creatorcontrib>Zhou, Liqun</creatorcontrib><creatorcontrib>Yao, Lin</creatorcontrib><creatorcontrib>Yue, Shuhua</creatorcontrib><title>VHL mutation drives human clear cell renal cell carcinoma progression through PI3K/AKT-dependent cholesteryl ester accumulation</title><title>EBioMedicine</title><addtitle>EBioMedicine</addtitle><description>Cholesteryl ester (CE) accumulation in intracellular lipid droplets (LDs) is an essential signature of clear cell renal cell carcinoma (ccRCC), but its molecular mechanism and pathological significance remain elusive.
Enabled by the label-free Raman spectromicroscopy, which integrated stimulated Raman scattering microscopy with confocal Raman spectroscopy on the same platform, we quantitatively analyzed LD distribution and composition at the single cell level in intact ccRCC cell and tissue specimens in situ without any processing or exogenous labeling. Since we found that commonly used ccRCC cell lines actually did not show the CE-rich signature, primary cancer cells were isolated from human tissues to retain the lipid signature of ccRCC with CE level as high as the original tissue, which offers a preferable cell model for the study of cholesterol metabolism in ccRCC. Moreover, we established a patient-derived xenograft (PDX) mouse model that retained the CE-rich phenotype of human ccRCC.
Surprisingly, our results revealed that CE accumulation was induced by tumor suppressor VHL mutation, the most common mutation of ccRCC. Moreover, VHL mutation was found to promote CE accumulation by upregulating HIFα and subsequent PI3K/AKT/mTOR/SREBPs pathway. Inspiringly, inhibition of cholesterol esterification remarkably suppressed ccRCC aggressiveness in vitro and in vivo with negligible toxicity, through the reduced membrane cholesterol-mediated downregulations of integrin and MAPK signaling pathways.
Collectively, our study improves current understanding of the role of CE accumulation in ccRCC and opens up new opportunities for treatment.
This work was supported by National Natural Science Foundation of China (No. U23B2046 and No. 62027824), National Key R&D Program of China (No. 2023YFC2415500), Fundamental Research Funds for the Central Universities (No. YWF-22-L-547), PKU-Baidu Fund (No. 2020BD033), Peking University First Hospital Scientific and Technological Achievement Transformation Incubation Guidance Fund (No. 2022CX02), and Beijing Municipal Health Commission (No. 2020-2Z-40713).</description><subject>Animals</subject><subject>Carcinoma, Renal Cell - genetics</subject><subject>Carcinoma, Renal Cell - metabolism</subject><subject>Carcinoma, Renal Cell - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cholesterol Esters - metabolism</subject><subject>Cholesterol metabolism</subject><subject>Clear cell renal cell carcinoma</subject><subject>Disease Models, Animal</subject><subject>Disease Progression</subject><subject>Humans</subject><subject>Kidney Neoplasms - genetics</subject><subject>Kidney Neoplasms - metabolism</subject><subject>Kidney Neoplasms - pathology</subject><subject>Mice</subject><subject>Mutation</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Raman spectromicroscopy</subject><subject>Signal Transduction</subject><subject>Stimulated Raman scattering microscopy</subject><subject>VHL mutation</subject><subject>Von Hippel-Lindau Tumor Suppressor Protein - genetics</subject><subject>Von Hippel-Lindau Tumor Suppressor Protein - metabolism</subject><issn>2352-3964</issn><issn>2352-3964</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1v2zAMNYYNa9H1FwwYdNwlqb5jH4ahKLq1aIDt0O0qMDSdKLCtTLID9LS_PiVui_ayC0lQj-9RfEXxUfC54MJebOe08qGbSy517hi-4G-KU6mMnKnK6rcv6pPiPKUt51wYnZvl--JElcbqUi5Oi7-_b5asGwcYfOhZHf2eEtuMHfQMW4LIkNqWReqhnUqEiL4PHbBdDOtIKR0Gh00M43rDft6qu4vLu_tZTTvqa-oHhpvQUhooPrTsmBkgjt3YHiU_FO8aaBOdP-az4te36_urm9nyx_fbq8vlDLXlQ46ltEob4DlqYcoaK0C-0qAAG9sI1EZWVVOXspQgF7UhWHGpCAWCXhh1VnydeHfjqqMa82YRWreLvoP44AJ49_ql9xu3DnsneFVV1pSZ4fMjQwx_xvwT1_l0OAn0FMbkFFfCWqmsyFA1QTGGlCI1zzqCu4N9buuO9rmDfW6yL099erni88yTWRnwZQJQPtTeU3QJPfVItY-Eg6uD_6_APxdnrzw</recordid><startdate>20240501</startdate><enddate>20240501</enddate><creator>Zhang, Shuo</creator><creator>Fang, Tinghe</creator><creator>He, Yexuan</creator><creator>Feng, Weichen</creator><creator>Yu, Zhuoyang</creator><creator>Zheng, Yaoyao</creator><creator>Zhang, Chi</creator><creator>Hu, Shuai</creator><creator>Liu, Zhuojun</creator><creator>Liu, Jia</creator><creator>Yu, Jian</creator><creator>Zhang, Han</creator><creator>He, Anbang</creator><creator>Gong, Yanqing</creator><creator>He, Zhisong</creator><creator>Yang, Kaiwei</creator><creator>Xi, Zhijun</creator><creator>Yu, Wei</creator><creator>Zhou, Liqun</creator><creator>Yao, Lin</creator><creator>Yue, Shuhua</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</scope><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>5PM</scope><orcidid>https://orcid.org/0000-0003-3889-3329</orcidid><orcidid>https://orcid.org/0000-0003-1830-008X</orcidid></search><sort><creationdate>20240501</creationdate><title>VHL mutation drives human clear cell renal cell carcinoma progression through PI3K/AKT-dependent cholesteryl ester accumulation</title><author>Zhang, Shuo ; Fang, Tinghe ; He, Yexuan ; Feng, Weichen ; Yu, Zhuoyang ; Zheng, Yaoyao ; Zhang, Chi ; Hu, Shuai ; Liu, Zhuojun ; Liu, Jia ; Yu, Jian ; Zhang, Han ; He, Anbang ; Gong, Yanqing ; He, Zhisong ; Yang, Kaiwei ; Xi, Zhijun ; Yu, Wei ; Zhou, Liqun ; Yao, Lin ; Yue, Shuhua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c460t-c4826345a06344158dc9ac0b4a3acf6f1c45299fd8282a27d5eab023ec1ca4753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Carcinoma, Renal Cell - genetics</topic><topic>Carcinoma, Renal Cell - metabolism</topic><topic>Carcinoma, Renal Cell - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cholesterol Esters - metabolism</topic><topic>Cholesterol metabolism</topic><topic>Clear cell renal cell carcinoma</topic><topic>Disease Models, Animal</topic><topic>Disease Progression</topic><topic>Humans</topic><topic>Kidney Neoplasms - genetics</topic><topic>Kidney Neoplasms - metabolism</topic><topic>Kidney Neoplasms - pathology</topic><topic>Mice</topic><topic>Mutation</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Raman spectromicroscopy</topic><topic>Signal Transduction</topic><topic>Stimulated Raman scattering microscopy</topic><topic>VHL mutation</topic><topic>Von Hippel-Lindau Tumor Suppressor Protein - genetics</topic><topic>Von Hippel-Lindau Tumor Suppressor Protein - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Shuo</creatorcontrib><creatorcontrib>Fang, Tinghe</creatorcontrib><creatorcontrib>He, Yexuan</creatorcontrib><creatorcontrib>Feng, Weichen</creatorcontrib><creatorcontrib>Yu, Zhuoyang</creatorcontrib><creatorcontrib>Zheng, Yaoyao</creatorcontrib><creatorcontrib>Zhang, Chi</creatorcontrib><creatorcontrib>Hu, Shuai</creatorcontrib><creatorcontrib>Liu, Zhuojun</creatorcontrib><creatorcontrib>Liu, Jia</creatorcontrib><creatorcontrib>Yu, Jian</creatorcontrib><creatorcontrib>Zhang, Han</creatorcontrib><creatorcontrib>He, Anbang</creatorcontrib><creatorcontrib>Gong, Yanqing</creatorcontrib><creatorcontrib>He, Zhisong</creatorcontrib><creatorcontrib>Yang, Kaiwei</creatorcontrib><creatorcontrib>Xi, Zhijun</creatorcontrib><creatorcontrib>Yu, Wei</creatorcontrib><creatorcontrib>Zhou, Liqun</creatorcontrib><creatorcontrib>Yao, Lin</creatorcontrib><creatorcontrib>Yue, Shuhua</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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>PubMed Central (Full Participant titles)</collection><jtitle>EBioMedicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Shuo</au><au>Fang, Tinghe</au><au>He, Yexuan</au><au>Feng, Weichen</au><au>Yu, Zhuoyang</au><au>Zheng, Yaoyao</au><au>Zhang, Chi</au><au>Hu, Shuai</au><au>Liu, Zhuojun</au><au>Liu, Jia</au><au>Yu, Jian</au><au>Zhang, Han</au><au>He, Anbang</au><au>Gong, Yanqing</au><au>He, Zhisong</au><au>Yang, Kaiwei</au><au>Xi, Zhijun</au><au>Yu, Wei</au><au>Zhou, Liqun</au><au>Yao, Lin</au><au>Yue, Shuhua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>VHL mutation drives human clear cell renal cell carcinoma progression through PI3K/AKT-dependent cholesteryl ester accumulation</atitle><jtitle>EBioMedicine</jtitle><addtitle>EBioMedicine</addtitle><date>2024-05-01</date><risdate>2024</risdate><volume>103</volume><spage>105070</spage><pages>105070-</pages><artnum>105070</artnum><issn>2352-3964</issn><eissn>2352-3964</eissn><abstract>Cholesteryl ester (CE) accumulation in intracellular lipid droplets (LDs) is an essential signature of clear cell renal cell carcinoma (ccRCC), but its molecular mechanism and pathological significance remain elusive.
Enabled by the label-free Raman spectromicroscopy, which integrated stimulated Raman scattering microscopy with confocal Raman spectroscopy on the same platform, we quantitatively analyzed LD distribution and composition at the single cell level in intact ccRCC cell and tissue specimens in situ without any processing or exogenous labeling. Since we found that commonly used ccRCC cell lines actually did not show the CE-rich signature, primary cancer cells were isolated from human tissues to retain the lipid signature of ccRCC with CE level as high as the original tissue, which offers a preferable cell model for the study of cholesterol metabolism in ccRCC. Moreover, we established a patient-derived xenograft (PDX) mouse model that retained the CE-rich phenotype of human ccRCC.
Surprisingly, our results revealed that CE accumulation was induced by tumor suppressor VHL mutation, the most common mutation of ccRCC. Moreover, VHL mutation was found to promote CE accumulation by upregulating HIFα and subsequent PI3K/AKT/mTOR/SREBPs pathway. Inspiringly, inhibition of cholesterol esterification remarkably suppressed ccRCC aggressiveness in vitro and in vivo with negligible toxicity, through the reduced membrane cholesterol-mediated downregulations of integrin and MAPK signaling pathways.
Collectively, our study improves current understanding of the role of CE accumulation in ccRCC and opens up new opportunities for treatment.
This work was supported by National Natural Science Foundation of China (No. U23B2046 and No. 62027824), National Key R&D Program of China (No. 2023YFC2415500), Fundamental Research Funds for the Central Universities (No. YWF-22-L-547), PKU-Baidu Fund (No. 2020BD033), Peking University First Hospital Scientific and Technological Achievement Transformation Incubation Guidance Fund (No. 2022CX02), and Beijing Municipal Health Commission (No. 2020-2Z-40713).</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>38564827</pmid><doi>10.1016/j.ebiom.2024.105070</doi><orcidid>https://orcid.org/0000-0003-3889-3329</orcidid><orcidid>https://orcid.org/0000-0003-1830-008X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Carcinoma, Renal Cell - genetics Carcinoma, Renal Cell - metabolism Carcinoma, Renal Cell - pathology Cell Line, Tumor Cholesterol Esters - metabolism Cholesterol metabolism Clear cell renal cell carcinoma Disease Models, Animal Disease Progression Humans Kidney Neoplasms - genetics Kidney Neoplasms - metabolism Kidney Neoplasms - pathology Mice Mutation Phosphatidylinositol 3-Kinases - metabolism Proto-Oncogene Proteins c-akt - metabolism Raman spectromicroscopy Signal Transduction Stimulated Raman scattering microscopy VHL mutation Von Hippel-Lindau Tumor Suppressor Protein - genetics Von Hippel-Lindau Tumor Suppressor Protein - metabolism |
| title | VHL mutation drives human clear cell renal cell carcinoma progression through PI3K/AKT-dependent cholesteryl ester accumulation |
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