CAIX Regulates GBM Motility and TAM Adhesion and Polarization through EGFR/STAT3 under Hypoxic Conditions
Carbonic anhydrases (CAs) are acid-base regulatory proteins that modulate a variety of physiological functions. Recent findings have shown that CAIX is particularly upregulated in glioblastoma multiforme (GBM) and is associated with a poor patient outcome and survival rate. An analysis of the GSE429...
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description | Carbonic anhydrases (CAs) are acid-base regulatory proteins that modulate a variety of physiological functions. Recent findings have shown that CAIX is particularly upregulated in glioblastoma multiforme (GBM) and is associated with a poor patient outcome and survival rate. An analysis of the GSE4290 dataset of patients with gliomas showed that CAIX was highly expressed in GBM and was negatively associated with prognosis. The expression of CAIX under hypoxic conditions in GBM significantly increased in protein, mRNA, and transcriptional activity. Importantly, CAIX upregulation also regulated GBM motility, monocyte adhesion to GBM, and the polarization of tumor-associated monocytes/macrophages (TAM). Furthermore, the overexpression of CAIX was observed in intracranial GBM cells. Additionally, epidermal growth factor receptor/signal transducer and activator of transcription 3 regulated CAIX expression under hypoxic conditions by affecting the stability of hypoxia-inducible factor 1 alpha. In contrast, the knockdown of CAIX dramatically abrogated the change in GBM motility and monocyte adhesion to GBM under hypoxic conditions. Our results provide a comprehensive understanding of the mechanisms of CAIX in the GBM microenvironment. Hence, novel therapeutic targets of GBM progression are possibly developed. |
doi_str_mv | 10.3390/ijms21165838 |
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Recent findings have shown that CAIX is particularly upregulated in glioblastoma multiforme (GBM) and is associated with a poor patient outcome and survival rate. An analysis of the GSE4290 dataset of patients with gliomas showed that CAIX was highly expressed in GBM and was negatively associated with prognosis. The expression of CAIX under hypoxic conditions in GBM significantly increased in protein, mRNA, and transcriptional activity. Importantly, CAIX upregulation also regulated GBM motility, monocyte adhesion to GBM, and the polarization of tumor-associated monocytes/macrophages (TAM). Furthermore, the overexpression of CAIX was observed in intracranial GBM cells. Additionally, epidermal growth factor receptor/signal transducer and activator of transcription 3 regulated CAIX expression under hypoxic conditions by affecting the stability of hypoxia-inducible factor 1 alpha. In contrast, the knockdown of CAIX dramatically abrogated the change in GBM motility and monocyte adhesion to GBM under hypoxic conditions. Our results provide a comprehensive understanding of the mechanisms of CAIX in the GBM microenvironment. Hence, novel therapeutic targets of GBM progression are possibly developed.</description><identifier>ISSN: 1661-6596</identifier><identifier>ISSN: 1422-0067</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms21165838</identifier><identifier>PMID: 32823915</identifier><language>eng</language><publisher>BASEL: Mdpi</publisher><subject>Acidosis ; Acids ; Adhesion ; Biochemistry & Molecular Biology ; Brain cancer ; Brain Neoplasms - enzymology ; Brain Neoplasms - pathology ; Breast cancer ; CAIX (carbonic anhydrase IX) ; Cancer therapies ; Carbon dioxide ; Carbonic Anhydrase IX - metabolism ; Cell Adhesion ; Cell growth ; Cell Line, Tumor ; Cell Movement ; Cell Polarity ; Chemistry ; Chemistry, Multidisciplinary ; Chemotherapy ; Cytotoxicity ; Datasets ; Epidermal growth factor ; Epidermal growth factor receptors ; ErbB Receptors - metabolism ; GBM (glioblastoma multiforme) ; Gene expression ; Glioblastoma ; Glioblastoma - enzymology ; Glioblastoma - pathology ; Growth factors ; Humans ; Hydrogen-Ion Concentration ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Hypoxia-inducible factor 1a ; Hypoxia-inducible factors ; hypoxic condition ; Kinases ; Life Sciences & Biomedicine ; M2 polarization ; Macrophages ; Medical prognosis ; Metabolism ; Metabolites ; Monocytes ; Monocytes - pathology ; Motility ; Pancreatic cancer ; Physical Sciences ; Physiology ; Polarization ; Protein expression ; Proteins ; Regulatory proteins ; Science & Technology ; Stat3 protein ; STAT3 Transcription Factor - metabolism ; Transcription ; Tumor Hypoxia ; Tumor Microenvironment ; Tumor-Associated Macrophages - enzymology ; Tumor-Associated Macrophages - pathology ; Tumors ; Vascular endothelial growth factor</subject><ispartof>International journal of molecular sciences, 2020-08, Vol.21 (16), p.5838, Article 5838</ispartof><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>20</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000565166600001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c478t-f427385d049adb91a0a47f952c9d0aa064a1b3e30a46616324d2871e13103c9a3</citedby><cites>FETCH-LOGICAL-c478t-f427385d049adb91a0a47f952c9d0aa064a1b3e30a46616324d2871e13103c9a3</cites><orcidid>0000-0002-4463-5919</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/PMC7461579/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461579/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,887,27931,27932,28255,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32823915$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Bor-Ren</creatorcontrib><creatorcontrib>Liu, Yu-Shu</creatorcontrib><creatorcontrib>Lai, Sheng-Wei</creatorcontrib><creatorcontrib>Lin, Hui-Jung</creatorcontrib><creatorcontrib>Shen, Ching-Kai</creatorcontrib><creatorcontrib>Yang, Liang-Yo</creatorcontrib><creatorcontrib>Lu, Dah-Yuu</creatorcontrib><title>CAIX Regulates GBM Motility and TAM Adhesion and Polarization through EGFR/STAT3 under Hypoxic Conditions</title><title>International journal of molecular sciences</title><addtitle>INT J MOL SCI</addtitle><addtitle>Int J Mol Sci</addtitle><description>Carbonic anhydrases (CAs) are acid-base regulatory proteins that modulate a variety of physiological functions. Recent findings have shown that CAIX is particularly upregulated in glioblastoma multiforme (GBM) and is associated with a poor patient outcome and survival rate. An analysis of the GSE4290 dataset of patients with gliomas showed that CAIX was highly expressed in GBM and was negatively associated with prognosis. The expression of CAIX under hypoxic conditions in GBM significantly increased in protein, mRNA, and transcriptional activity. Importantly, CAIX upregulation also regulated GBM motility, monocyte adhesion to GBM, and the polarization of tumor-associated monocytes/macrophages (TAM). Furthermore, the overexpression of CAIX was observed in intracranial GBM cells. Additionally, epidermal growth factor receptor/signal transducer and activator of transcription 3 regulated CAIX expression under hypoxic conditions by affecting the stability of hypoxia-inducible factor 1 alpha. In contrast, the knockdown of CAIX dramatically abrogated the change in GBM motility and monocyte adhesion to GBM under hypoxic conditions. Our results provide a comprehensive understanding of the mechanisms of CAIX in the GBM microenvironment. Hence, novel therapeutic targets of GBM progression are possibly developed.</description><subject>Acidosis</subject><subject>Acids</subject><subject>Adhesion</subject><subject>Biochemistry & Molecular Biology</subject><subject>Brain cancer</subject><subject>Brain Neoplasms - enzymology</subject><subject>Brain Neoplasms - pathology</subject><subject>Breast cancer</subject><subject>CAIX (carbonic anhydrase IX)</subject><subject>Cancer therapies</subject><subject>Carbon dioxide</subject><subject>Carbonic Anhydrase IX - metabolism</subject><subject>Cell Adhesion</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement</subject><subject>Cell Polarity</subject><subject>Chemistry</subject><subject>Chemistry, Multidisciplinary</subject><subject>Chemotherapy</subject><subject>Cytotoxicity</subject><subject>Datasets</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>ErbB Receptors - metabolism</subject><subject>GBM (glioblastoma multiforme)</subject><subject>Gene expression</subject><subject>Glioblastoma</subject><subject>Glioblastoma - enzymology</subject><subject>Glioblastoma - pathology</subject><subject>Growth factors</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Hypoxia</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</subject><subject>Hypoxia-inducible factor 1a</subject><subject>Hypoxia-inducible factors</subject><subject>hypoxic condition</subject><subject>Kinases</subject><subject>Life Sciences & Biomedicine</subject><subject>M2 polarization</subject><subject>Macrophages</subject><subject>Medical prognosis</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Monocytes</subject><subject>Monocytes - pathology</subject><subject>Motility</subject><subject>Pancreatic cancer</subject><subject>Physical Sciences</subject><subject>Physiology</subject><subject>Polarization</subject><subject>Protein expression</subject><subject>Proteins</subject><subject>Regulatory proteins</subject><subject>Science & Technology</subject><subject>Stat3 protein</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Transcription</subject><subject>Tumor Hypoxia</subject><subject>Tumor Microenvironment</subject><subject>Tumor-Associated Macrophages - enzymology</subject><subject>Tumor-Associated Macrophages - pathology</subject><subject>Tumors</subject><subject>Vascular endothelial growth factor</subject><issn>1661-6596</issn><issn>1422-0067</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>AOWDO</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><sourceid>DOA</sourceid><recordid>eNqNkktvEzEUhUcIRB-wY41GYoMEQ_1-bJDCqE0jNQKVILGznLEncTQZB9tDCb8eJylRy4qVr46_e3SvfYriFQQfMJbgwq3WEUHIqMDiSXEKCUIVAIw_zTVjsGJUspPiLMYVAAgjKp8XJxgJhCWkp4WrR5Pv5a1dDJ1ONpbjT9Ny6pPrXNqWujflbDQtR2Zpo_P9XvjiOx3cb512QloGPyyW5eX46vbi62w0w-XQGxvK6-3G_3JNWfveuB0aXxTPWt1F-_L-PC--XV3O6uvq5vN4Uo9uqoZwkaqWII4FNYBIbeYSaqAJbyVFjTRAa8CIhnNscZbzdgwjYpDg0EIMAW6kxufF5OBrvF6pTXBrHbbKa6f2gg8LpUNyTWcVEZgxroEhHBMm5kJQ1hoNTasJFZxkr48Hr80wX1vT2D4F3T0yfXzTu6Va-J-KEwYpl9ng7b1B8D8GG5Nau9jYrtO99UNUiGCGJZEcZfTNP-jKD6HPT7WjKEYSyB31_kA1wccYbHscBgK1y4N6mIeMv364wBH-G4AMiANwZ-e-jY2zfWOPGACAMppjxHIFYO3S_ttrP_Qpt777_1b8B8K9zzo</recordid><startdate>20200814</startdate><enddate>20200814</enddate><creator>Huang, Bor-Ren</creator><creator>Liu, Yu-Shu</creator><creator>Lai, Sheng-Wei</creator><creator>Lin, Hui-Jung</creator><creator>Shen, Ching-Kai</creator><creator>Yang, Liang-Yo</creator><creator>Lu, Dah-Yuu</creator><general>Mdpi</general><general>MDPI AG</general><general>MDPI</general><scope>AOWDO</scope><scope>BLEPL</scope><scope>DTL</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</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>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-4463-5919</orcidid></search><sort><creationdate>20200814</creationdate><title>CAIX Regulates GBM Motility and TAM Adhesion and Polarization through EGFR/STAT3 under Hypoxic Conditions</title><author>Huang, Bor-Ren ; Liu, Yu-Shu ; Lai, Sheng-Wei ; Lin, Hui-Jung ; Shen, Ching-Kai ; Yang, Liang-Yo ; Lu, Dah-Yuu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c478t-f427385d049adb91a0a47f952c9d0aa064a1b3e30a46616324d2871e13103c9a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Acidosis</topic><topic>Acids</topic><topic>Adhesion</topic><topic>Biochemistry & Molecular Biology</topic><topic>Brain cancer</topic><topic>Brain Neoplasms - enzymology</topic><topic>Brain Neoplasms - pathology</topic><topic>Breast cancer</topic><topic>CAIX (carbonic anhydrase IX)</topic><topic>Cancer therapies</topic><topic>Carbon dioxide</topic><topic>Carbonic Anhydrase IX - metabolism</topic><topic>Cell Adhesion</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement</topic><topic>Cell Polarity</topic><topic>Chemistry</topic><topic>Chemistry, Multidisciplinary</topic><topic>Chemotherapy</topic><topic>Cytotoxicity</topic><topic>Datasets</topic><topic>Epidermal growth factor</topic><topic>Epidermal growth factor receptors</topic><topic>ErbB Receptors - metabolism</topic><topic>GBM (glioblastoma multiforme)</topic><topic>Gene expression</topic><topic>Glioblastoma</topic><topic>Glioblastoma - enzymology</topic><topic>Glioblastoma - pathology</topic><topic>Growth factors</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Hypoxia</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</topic><topic>Hypoxia-inducible factor 1a</topic><topic>Hypoxia-inducible factors</topic><topic>hypoxic condition</topic><topic>Kinases</topic><topic>Life Sciences & Biomedicine</topic><topic>M2 polarization</topic><topic>Macrophages</topic><topic>Medical prognosis</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Monocytes</topic><topic>Monocytes - pathology</topic><topic>Motility</topic><topic>Pancreatic cancer</topic><topic>Physical Sciences</topic><topic>Physiology</topic><topic>Polarization</topic><topic>Protein expression</topic><topic>Proteins</topic><topic>Regulatory proteins</topic><topic>Science & Technology</topic><topic>Stat3 protein</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Transcription</topic><topic>Tumor Hypoxia</topic><topic>Tumor Microenvironment</topic><topic>Tumor-Associated Macrophages - enzymology</topic><topic>Tumor-Associated Macrophages - pathology</topic><topic>Tumors</topic><topic>Vascular endothelial growth factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Bor-Ren</creatorcontrib><creatorcontrib>Liu, Yu-Shu</creatorcontrib><creatorcontrib>Lai, Sheng-Wei</creatorcontrib><creatorcontrib>Lin, Hui-Jung</creatorcontrib><creatorcontrib>Shen, Ching-Kai</creatorcontrib><creatorcontrib>Yang, Liang-Yo</creatorcontrib><creatorcontrib>Lu, Dah-Yuu</creatorcontrib><collection>Web of Science - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Bor-Ren</au><au>Liu, Yu-Shu</au><au>Lai, Sheng-Wei</au><au>Lin, Hui-Jung</au><au>Shen, Ching-Kai</au><au>Yang, Liang-Yo</au><au>Lu, Dah-Yuu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CAIX Regulates GBM Motility and TAM Adhesion and Polarization through EGFR/STAT3 under Hypoxic Conditions</atitle><jtitle>International journal of molecular sciences</jtitle><stitle>INT J MOL SCI</stitle><addtitle>Int J Mol Sci</addtitle><date>2020-08-14</date><risdate>2020</risdate><volume>21</volume><issue>16</issue><spage>5838</spage><pages>5838-</pages><artnum>5838</artnum><issn>1661-6596</issn><issn>1422-0067</issn><eissn>1422-0067</eissn><abstract>Carbonic anhydrases (CAs) are acid-base regulatory proteins that modulate a variety of physiological functions. Recent findings have shown that CAIX is particularly upregulated in glioblastoma multiforme (GBM) and is associated with a poor patient outcome and survival rate. An analysis of the GSE4290 dataset of patients with gliomas showed that CAIX was highly expressed in GBM and was negatively associated with prognosis. The expression of CAIX under hypoxic conditions in GBM significantly increased in protein, mRNA, and transcriptional activity. Importantly, CAIX upregulation also regulated GBM motility, monocyte adhesion to GBM, and the polarization of tumor-associated monocytes/macrophages (TAM). Furthermore, the overexpression of CAIX was observed in intracranial GBM cells. Additionally, epidermal growth factor receptor/signal transducer and activator of transcription 3 regulated CAIX expression under hypoxic conditions by affecting the stability of hypoxia-inducible factor 1 alpha. In contrast, the knockdown of CAIX dramatically abrogated the change in GBM motility and monocyte adhesion to GBM under hypoxic conditions. Our results provide a comprehensive understanding of the mechanisms of CAIX in the GBM microenvironment. Hence, novel therapeutic targets of GBM progression are possibly developed.</abstract><cop>BASEL</cop><pub>Mdpi</pub><pmid>32823915</pmid><doi>10.3390/ijms21165838</doi><tpages>24</tpages><orcidid>https://orcid.org/0000-0002-4463-5919</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Acidosis Acids Adhesion Biochemistry & Molecular Biology Brain cancer Brain Neoplasms - enzymology Brain Neoplasms - pathology Breast cancer CAIX (carbonic anhydrase IX) Cancer therapies Carbon dioxide Carbonic Anhydrase IX - metabolism Cell Adhesion Cell growth Cell Line, Tumor Cell Movement Cell Polarity Chemistry Chemistry, Multidisciplinary Chemotherapy Cytotoxicity Datasets Epidermal growth factor Epidermal growth factor receptors ErbB Receptors - metabolism GBM (glioblastoma multiforme) Gene expression Glioblastoma Glioblastoma - enzymology Glioblastoma - pathology Growth factors Humans Hydrogen-Ion Concentration Hypoxia Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Hypoxia-inducible factor 1a Hypoxia-inducible factors hypoxic condition Kinases Life Sciences & Biomedicine M2 polarization Macrophages Medical prognosis Metabolism Metabolites Monocytes Monocytes - pathology Motility Pancreatic cancer Physical Sciences Physiology Polarization Protein expression Proteins Regulatory proteins Science & Technology Stat3 protein STAT3 Transcription Factor - metabolism Transcription Tumor Hypoxia Tumor Microenvironment Tumor-Associated Macrophages - enzymology Tumor-Associated Macrophages - pathology Tumors Vascular endothelial growth factor |
title | CAIX Regulates GBM Motility and TAM Adhesion and Polarization through EGFR/STAT3 under Hypoxic Conditions |
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