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CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma
Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC. CD73 expression modulatio...
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Published in: | Journal of hematology and oncology 2020-02, Vol.13 (1), p.11-11, Article 11 |
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description | Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC.
CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation.
We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73- counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3β. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis.
Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC. |
doi_str_mv | 10.1186/s13045-020-0845-z |
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CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation.
We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73- counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3β. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis.
Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.</description><identifier>ISSN: 1756-8722</identifier><identifier>EISSN: 1756-8722</identifier><identifier>DOI: 10.1186/s13045-020-0845-z</identifier><identifier>PMID: 32024555</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>5'-Nucleotidase - genetics ; AKT protein ; AKT signaling ; Analysis ; Animal models ; Biochemistry ; c-Myc protein ; Cancer ; Cancer stem cells ; Cancer therapies ; Carcinoma ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - pathology ; CD73 ; CD73 antigen ; Cell differentiation ; Cell Line, Tumor ; Development and progression ; Drug resistance ; Experiments ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genes ; Genetic research ; Glycogen ; Glycogen synthase kinase 3 ; Glycogen synthesis ; GPI-Linked Proteins - genetics ; Hematology ; Hepatocellular carcinoma ; Humans ; Immunoprecipitation ; Infection ; Kinases ; Laboratory animals ; Lenvatinib ; Lenvatinib resistance ; Liver cancer ; Liver Neoplasms - genetics ; Liver Neoplasms - pathology ; Medical prognosis ; Metastasis ; Myc protein ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Oncology ; Polysaccharides ; Proteins ; Rap1 protein ; Sox9 protein ; SOX9 Transcription Factor - analysis ; SOX9 Transcription Factor - genetics ; Spheroids ; Stem cells ; Studies ; Transcription ; Tumors ; Ubiquitin</subject><ispartof>Journal of hematology and oncology, 2020-02, Vol.13 (1), p.11-11, Article 11</ispartof><rights>COPYRIGHT 2020 BioMed Central Ltd.</rights><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s). 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c591t-2b4eae6bf440b689558a49d7fddaf703140debd07b5f4fa3fab030135725ebe3</citedby><cites>FETCH-LOGICAL-c591t-2b4eae6bf440b689558a49d7fddaf703140debd07b5f4fa3fab030135725ebe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003355/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2357356354?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32024555$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ma, Xiao-Lu</creatorcontrib><creatorcontrib>Hu, Bo</creatorcontrib><creatorcontrib>Tang, Wei-Guo</creatorcontrib><creatorcontrib>Xie, Su-Hong</creatorcontrib><creatorcontrib>Ren, Ning</creatorcontrib><creatorcontrib>Guo, Lin</creatorcontrib><creatorcontrib>Lu, Ren-Quan</creatorcontrib><title>CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma</title><title>Journal of hematology and oncology</title><addtitle>J Hematol Oncol</addtitle><description>Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC.
CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation.
We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73- counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3β. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis.
Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.</description><subject>5'-Nucleotidase - genetics</subject><subject>AKT protein</subject><subject>AKT signaling</subject><subject>Analysis</subject><subject>Animal models</subject><subject>Biochemistry</subject><subject>c-Myc protein</subject><subject>Cancer</subject><subject>Cancer stem cells</subject><subject>Cancer therapies</subject><subject>Carcinoma</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>CD73</subject><subject>CD73 antigen</subject><subject>Cell differentiation</subject><subject>Cell Line, Tumor</subject><subject>Development and progression</subject><subject>Drug resistance</subject><subject>Experiments</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes</subject><subject>Genetic research</subject><subject>Glycogen</subject><subject>Glycogen synthase kinase 3</subject><subject>Glycogen synthesis</subject><subject>GPI-Linked Proteins - genetics</subject><subject>Hematology</subject><subject>Hepatocellular carcinoma</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Infection</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Lenvatinib</subject><subject>Lenvatinib resistance</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - pathology</subject><subject>Medical prognosis</subject><subject>Metastasis</subject><subject>Myc protein</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Oncology</subject><subject>Polysaccharides</subject><subject>Proteins</subject><subject>Rap1 protein</subject><subject>Sox9 protein</subject><subject>SOX9 Transcription Factor - analysis</subject><subject>SOX9 Transcription Factor - genetics</subject><subject>Spheroids</subject><subject>Stem cells</subject><subject>Studies</subject><subject>Transcription</subject><subject>Tumors</subject><subject>Ubiquitin</subject><issn>1756-8722</issn><issn>1756-8722</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNptkk1vFCEcxidGY2v1A3gxJCbGy1ReBmbmYtKsb02a9GAP3sgfBnZpZmAFxrj99DJurbvGcIDA8_wID09VvST4nJBOvEuE4YbXmOIad2Vx96g6JS0XdddS-vhgfVI9S-kWY0F6ip9WJ4xi2nDOT6tp9aFlKM0pg_NmQBq8NrFO2Uy1NuOIcgSXE1I7tI1hCtn5Nfp6_a1H5uc2mpRc8Aj8gApAudHlHXIebcwWclj88wixQKN2PkzwvHpiYUzmxf18Vt18-niz-lJfXX--XF1c1Zr3JNdUNQaMULZpsBJdz3kHTT-0dhjAtpiRBg9GDbhV3DYWmAWFGSaMt5QbZdhZdbnHDgFu5Ta6CeJOBnDy90aIawkxOz0aabUF6AbFRKeaDjQQ3VEqKAglek54Yb3fs7azmsygjS-JjEfQ4xPvNnIdfsgWY8b4Anh7D4jh-2xSlpNLSzTgTZiTpIxTzMt_4CJ9_Y_0NszRl6QWVcu4YLz5q1pDeYDzNpR79QKVF4KIhhBGRVGd_0dVxmAmp4M31pX9I8ObA8PGwJg3KYxzLj-cjoVkL9QxpBSNfQiDYLn0Uu57KUsv5dJLeVc8rw5TfHD8KSL7Bdwn3eE</recordid><startdate>20200205</startdate><enddate>20200205</enddate><creator>Ma, Xiao-Lu</creator><creator>Hu, Bo</creator><creator>Tang, Wei-Guo</creator><creator>Xie, Su-Hong</creator><creator>Ren, Ning</creator><creator>Guo, Lin</creator><creator>Lu, Ren-Quan</creator><general>BioMed Central Ltd</general><general>BioMed Central</general><general>BMC</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>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20200205</creationdate><title>CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma</title><author>Ma, Xiao-Lu ; Hu, Bo ; Tang, Wei-Guo ; Xie, Su-Hong ; Ren, Ning ; Guo, Lin ; Lu, Ren-Quan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c591t-2b4eae6bf440b689558a49d7fddaf703140debd07b5f4fa3fab030135725ebe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>5'-Nucleotidase - genetics</topic><topic>AKT protein</topic><topic>AKT signaling</topic><topic>Analysis</topic><topic>Animal models</topic><topic>Biochemistry</topic><topic>c-Myc protein</topic><topic>Cancer</topic><topic>Cancer stem cells</topic><topic>Cancer therapies</topic><topic>Carcinoma</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>CD73</topic><topic>CD73 antigen</topic><topic>Cell differentiation</topic><topic>Cell Line, Tumor</topic><topic>Development and progression</topic><topic>Drug resistance</topic><topic>Experiments</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genes</topic><topic>Genetic research</topic><topic>Glycogen</topic><topic>Glycogen synthase kinase 3</topic><topic>Glycogen synthesis</topic><topic>GPI-Linked Proteins - genetics</topic><topic>Hematology</topic><topic>Hepatocellular carcinoma</topic><topic>Humans</topic><topic>Immunoprecipitation</topic><topic>Infection</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>Lenvatinib</topic><topic>Lenvatinib resistance</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - pathology</topic><topic>Medical prognosis</topic><topic>Metastasis</topic><topic>Myc protein</topic><topic>Neoplastic Stem Cells - metabolism</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>Oncology</topic><topic>Polysaccharides</topic><topic>Proteins</topic><topic>Rap1 protein</topic><topic>Sox9 protein</topic><topic>SOX9 Transcription Factor - analysis</topic><topic>SOX9 Transcription Factor - genetics</topic><topic>Spheroids</topic><topic>Stem cells</topic><topic>Studies</topic><topic>Transcription</topic><topic>Tumors</topic><topic>Ubiquitin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ma, Xiao-Lu</creatorcontrib><creatorcontrib>Hu, Bo</creatorcontrib><creatorcontrib>Tang, Wei-Guo</creatorcontrib><creatorcontrib>Xie, Su-Hong</creatorcontrib><creatorcontrib>Ren, Ning</creatorcontrib><creatorcontrib>Guo, Lin</creatorcontrib><creatorcontrib>Lu, Ren-Quan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Complete (ProQuest Database)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>Journal of hematology and oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ma, Xiao-Lu</au><au>Hu, Bo</au><au>Tang, Wei-Guo</au><au>Xie, Su-Hong</au><au>Ren, Ning</au><au>Guo, Lin</au><au>Lu, Ren-Quan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma</atitle><jtitle>Journal of hematology and oncology</jtitle><addtitle>J Hematol Oncol</addtitle><date>2020-02-05</date><risdate>2020</risdate><volume>13</volume><issue>1</issue><spage>11</spage><epage>11</epage><pages>11-11</pages><artnum>11</artnum><issn>1756-8722</issn><eissn>1756-8722</eissn><abstract>Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC.
CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation.
We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73- counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3β. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis.
Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>32024555</pmid><doi>10.1186/s13045-020-0845-z</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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subjects | 5'-Nucleotidase - genetics AKT protein AKT signaling Analysis Animal models Biochemistry c-Myc protein Cancer Cancer stem cells Cancer therapies Carcinoma Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - pathology CD73 CD73 antigen Cell differentiation Cell Line, Tumor Development and progression Drug resistance Experiments Gene expression Gene Expression Regulation, Neoplastic Genes Genetic research Glycogen Glycogen synthase kinase 3 Glycogen synthesis GPI-Linked Proteins - genetics Hematology Hepatocellular carcinoma Humans Immunoprecipitation Infection Kinases Laboratory animals Lenvatinib Lenvatinib resistance Liver cancer Liver Neoplasms - genetics Liver Neoplasms - pathology Medical prognosis Metastasis Myc protein Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Oncology Polysaccharides Proteins Rap1 protein Sox9 protein SOX9 Transcription Factor - analysis SOX9 Transcription Factor - genetics Spheroids Stem cells Studies Transcription Tumors Ubiquitin |
title | CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma |
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