FGF19 and FGFR4 promotes the progression of gallbladder carcinoma in an autocrine pathway dependent on GPBAR1-cAMP-EGR1 axis
Treatment options for gallbladder carcinoma (GBC) are limited and GBC prognosis remains poor. There is no well-accepted targeted therapy to date, so effective biomarkers of GBC are urgently needed. Here we investigated the expression and correlations of fibroblast growth factor receptors (FGFR1-4) a...
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| Veröffentlicht in: | Oncogene 2021-07, Vol.40 (30), p.4941-4953 |
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| creator | Chen, Tianli Liu, Hongda Liu, Zengli Li, Kangshuai Qin, Ruixi Wang, Yue Liu, Jialiang Li, Zhipeng Gao, Qinglun Pan, Chang Yang, Fan Zhao, Wei Zhang, Zongli Xu, Yunfei |
| description | Treatment options for gallbladder carcinoma (GBC) are limited and GBC prognosis remains poor. There is no well-accepted targeted therapy to date, so effective biomarkers of GBC are urgently needed. Here we investigated the expression and correlations of fibroblast growth factor receptors (FGFR1-4) and 18 fibroblast growth factors (FGFs) in two independent patient cohorts and evaluated their prognostic significance. Consequently, we demonstrated that both FGF19 and FGFR4 were unfavorable prognostic biomarkers, and their co-expression was a more sensitive predictor. By analyzing the correlations between all 18 FGFs and FGFR4, we showed that FGF19 expression was significantly associated with FGFR4 and promoted GBC progression via stimulating FGFR4. With experiments using GBC cells, GPBAR1
−/−
mice models, and human subjects, we demonstrated that elevated bile acids (BAs) could increase the transcription and expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. FGF19 secreted from GBC cells promoted GBC progression by stimulating FGFR4 and downstream ERK in an autocrine manner with bile as a potential carrier. Patients with GBC had significantly higher FGF19 in serum and bile, compared to patients with cholelithiasis. BLU9931 inhibited FGFR4 and attenuated its oncogenic effects in GBC cell line. In conclusion, upregulation of BAs elevated co-expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. Co-expression of FGF19 and FGFR4 was a sensitive and unfavorable prognostic marker. GBC cells secreted FGF19 and facilitated progression by activating FGFR4 with bile as a potential carrier in an autocrine pathway. |
| doi_str_mv | 10.1038/s41388-021-01850-1 |
| format | Article |
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−/−
mice models, and human subjects, we demonstrated that elevated bile acids (BAs) could increase the transcription and expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. FGF19 secreted from GBC cells promoted GBC progression by stimulating FGFR4 and downstream ERK in an autocrine manner with bile as a potential carrier. Patients with GBC had significantly higher FGF19 in serum and bile, compared to patients with cholelithiasis. BLU9931 inhibited FGFR4 and attenuated its oncogenic effects in GBC cell line. In conclusion, upregulation of BAs elevated co-expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. Co-expression of FGF19 and FGFR4 was a sensitive and unfavorable prognostic marker. GBC cells secreted FGF19 and facilitated progression by activating FGFR4 with bile as a potential carrier in an autocrine pathway.</description><identifier>ISSN: 0950-9232</identifier><identifier>ISSN: 1476-5594</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-021-01850-1</identifier><identifier>PMID: 34163030</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/105 ; 13/109 ; 13/89 ; 13/95 ; 38/77 ; 38/91 ; 631/1647/514 ; 631/67/1504/1329 ; 64/110 ; 692/53/2422 ; Animal models ; Apoptosis ; Autocrine Communication ; Autocrine mechanisms ; Autocrine signalling ; Bile ; Bile acids ; Biomarkers ; Biomarkers, Tumor ; Cancer ; Cell Biology ; Cell culture ; Cell Line ; Cell Proliferation ; Cellular signal transduction ; Cyclic adenylic acid ; Cyclic AMP ; Cyclic AMP - metabolism ; Development and progression ; Disease Progression ; Disease Susceptibility ; Early Growth Response Protein 1 - metabolism ; EGR-1 protein ; Fibroblast growth factor receptor 1 ; Fibroblast growth factor receptor 4 ; Fibroblast growth factor receptors ; Fibroblast growth factors ; Fibroblast Growth Factors - metabolism ; Fibroblasts ; Gallbladder ; Gallbladder cancer ; Gallbladder Neoplasms - etiology ; Gallbladder Neoplasms - metabolism ; Gallbladder Neoplasms - mortality ; Gallbladder Neoplasms - pathology ; Gene Expression Regulation, Neoplastic ; Genetic aspects ; Growth factor receptors ; Health aspects ; Human Genetics ; Humans ; Internal Medicine ; Medicine ; Medicine & Public Health ; Oncology ; Oncology, Experimental ; Patients ; Prognosis ; Protein Binding ; Protein kinases ; Receptor, Fibroblast Growth Factor, Type 4 - metabolism ; Receptors, G-Protein-Coupled - metabolism ; RNA, Messenger ; Signal Transduction ; Transcription ; Transcription factors</subject><ispartof>Oncogene, 2021-07, Vol.40 (30), p.4941-4953</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021. corrected publication 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2021. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-372fc08683d5b327a247aa9fbba6ea87e1d7c85d0acac93fc616451690d3cb23</citedby><cites>FETCH-LOGICAL-c508t-372fc08683d5b327a247aa9fbba6ea87e1d7c85d0acac93fc616451690d3cb23</cites><orcidid>0000-0002-0580-7116 ; 0000-0002-9501-3757</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34163030$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Tianli</creatorcontrib><creatorcontrib>Liu, Hongda</creatorcontrib><creatorcontrib>Liu, Zengli</creatorcontrib><creatorcontrib>Li, Kangshuai</creatorcontrib><creatorcontrib>Qin, Ruixi</creatorcontrib><creatorcontrib>Wang, Yue</creatorcontrib><creatorcontrib>Liu, Jialiang</creatorcontrib><creatorcontrib>Li, Zhipeng</creatorcontrib><creatorcontrib>Gao, Qinglun</creatorcontrib><creatorcontrib>Pan, Chang</creatorcontrib><creatorcontrib>Yang, Fan</creatorcontrib><creatorcontrib>Zhao, Wei</creatorcontrib><creatorcontrib>Zhang, Zongli</creatorcontrib><creatorcontrib>Xu, Yunfei</creatorcontrib><title>FGF19 and FGFR4 promotes the progression of gallbladder carcinoma in an autocrine pathway dependent on GPBAR1-cAMP-EGR1 axis</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Treatment options for gallbladder carcinoma (GBC) are limited and GBC prognosis remains poor. There is no well-accepted targeted therapy to date, so effective biomarkers of GBC are urgently needed. Here we investigated the expression and correlations of fibroblast growth factor receptors (FGFR1-4) and 18 fibroblast growth factors (FGFs) in two independent patient cohorts and evaluated their prognostic significance. Consequently, we demonstrated that both FGF19 and FGFR4 were unfavorable prognostic biomarkers, and their co-expression was a more sensitive predictor. By analyzing the correlations between all 18 FGFs and FGFR4, we showed that FGF19 expression was significantly associated with FGFR4 and promoted GBC progression via stimulating FGFR4. With experiments using GBC cells, GPBAR1
−/−
mice models, and human subjects, we demonstrated that elevated bile acids (BAs) could increase the transcription and expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. FGF19 secreted from GBC cells promoted GBC progression by stimulating FGFR4 and downstream ERK in an autocrine manner with bile as a potential carrier. Patients with GBC had significantly higher FGF19 in serum and bile, compared to patients with cholelithiasis. BLU9931 inhibited FGFR4 and attenuated its oncogenic effects in GBC cell line. In conclusion, upregulation of BAs elevated co-expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. Co-expression of FGF19 and FGFR4 was a sensitive and unfavorable prognostic marker. GBC cells secreted FGF19 and facilitated progression by activating FGFR4 with bile as a potential carrier in an autocrine pathway.</description><subject>13/1</subject><subject>13/105</subject><subject>13/109</subject><subject>13/89</subject><subject>13/95</subject><subject>38/77</subject><subject>38/91</subject><subject>631/1647/514</subject><subject>631/67/1504/1329</subject><subject>64/110</subject><subject>692/53/2422</subject><subject>Animal models</subject><subject>Apoptosis</subject><subject>Autocrine Communication</subject><subject>Autocrine mechanisms</subject><subject>Autocrine signalling</subject><subject>Bile</subject><subject>Bile acids</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor</subject><subject>Cancer</subject><subject>Cell Biology</subject><subject>Cell culture</subject><subject>Cell Line</subject><subject>Cell Proliferation</subject><subject>Cellular signal transduction</subject><subject>Cyclic adenylic acid</subject><subject>Cyclic AMP</subject><subject>Cyclic AMP - metabolism</subject><subject>Development and progression</subject><subject>Disease Progression</subject><subject>Disease Susceptibility</subject><subject>Early Growth Response Protein 1 - metabolism</subject><subject>EGR-1 protein</subject><subject>Fibroblast growth factor receptor 1</subject><subject>Fibroblast growth factor receptor 4</subject><subject>Fibroblast growth factor receptors</subject><subject>Fibroblast growth factors</subject><subject>Fibroblast Growth Factors - metabolism</subject><subject>Fibroblasts</subject><subject>Gallbladder</subject><subject>Gallbladder cancer</subject><subject>Gallbladder Neoplasms - etiology</subject><subject>Gallbladder Neoplasms - metabolism</subject><subject>Gallbladder Neoplasms - mortality</subject><subject>Gallbladder Neoplasms - pathology</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genetic aspects</subject><subject>Growth factor receptors</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Oncology</subject><subject>Oncology, Experimental</subject><subject>Patients</subject><subject>Prognosis</subject><subject>Protein Binding</subject><subject>Protein kinases</subject><subject>Receptor, Fibroblast Growth Factor, Type 4 - 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metabolism</topic><topic>Development and progression</topic><topic>Disease Progression</topic><topic>Disease Susceptibility</topic><topic>Early Growth Response Protein 1 - metabolism</topic><topic>EGR-1 protein</topic><topic>Fibroblast growth factor receptor 1</topic><topic>Fibroblast growth factor receptor 4</topic><topic>Fibroblast growth factor receptors</topic><topic>Fibroblast growth factors</topic><topic>Fibroblast Growth Factors - metabolism</topic><topic>Fibroblasts</topic><topic>Gallbladder</topic><topic>Gallbladder cancer</topic><topic>Gallbladder Neoplasms - etiology</topic><topic>Gallbladder Neoplasms - metabolism</topic><topic>Gallbladder Neoplasms - mortality</topic><topic>Gallbladder Neoplasms - pathology</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genetic aspects</topic><topic>Growth factor receptors</topic><topic>Health aspects</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Oncology</topic><topic>Oncology, Experimental</topic><topic>Patients</topic><topic>Prognosis</topic><topic>Protein Binding</topic><topic>Protein kinases</topic><topic>Receptor, Fibroblast Growth Factor, Type 4 - 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Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Tianli</au><au>Liu, Hongda</au><au>Liu, Zengli</au><au>Li, Kangshuai</au><au>Qin, Ruixi</au><au>Wang, Yue</au><au>Liu, Jialiang</au><au>Li, Zhipeng</au><au>Gao, Qinglun</au><au>Pan, Chang</au><au>Yang, Fan</au><au>Zhao, Wei</au><au>Zhang, Zongli</au><au>Xu, Yunfei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FGF19 and FGFR4 promotes the progression of gallbladder carcinoma in an autocrine pathway dependent on GPBAR1-cAMP-EGR1 axis</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2021-07-29</date><risdate>2021</risdate><volume>40</volume><issue>30</issue><spage>4941</spage><epage>4953</epage><pages>4941-4953</pages><issn>0950-9232</issn><issn>1476-5594</issn><eissn>1476-5594</eissn><abstract>Treatment options for gallbladder carcinoma (GBC) are limited and GBC prognosis remains poor. There is no well-accepted targeted therapy to date, so effective biomarkers of GBC are urgently needed. Here we investigated the expression and correlations of fibroblast growth factor receptors (FGFR1-4) and 18 fibroblast growth factors (FGFs) in two independent patient cohorts and evaluated their prognostic significance. Consequently, we demonstrated that both FGF19 and FGFR4 were unfavorable prognostic biomarkers, and their co-expression was a more sensitive predictor. By analyzing the correlations between all 18 FGFs and FGFR4, we showed that FGF19 expression was significantly associated with FGFR4 and promoted GBC progression via stimulating FGFR4. With experiments using GBC cells, GPBAR1
−/−
mice models, and human subjects, we demonstrated that elevated bile acids (BAs) could increase the transcription and expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. FGF19 secreted from GBC cells promoted GBC progression by stimulating FGFR4 and downstream ERK in an autocrine manner with bile as a potential carrier. Patients with GBC had significantly higher FGF19 in serum and bile, compared to patients with cholelithiasis. BLU9931 inhibited FGFR4 and attenuated its oncogenic effects in GBC cell line. In conclusion, upregulation of BAs elevated co-expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. Co-expression of FGF19 and FGFR4 was a sensitive and unfavorable prognostic marker. GBC cells secreted FGF19 and facilitated progression by activating FGFR4 with bile as a potential carrier in an autocrine pathway.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34163030</pmid><doi>10.1038/s41388-021-01850-1</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-0580-7116</orcidid><orcidid>https://orcid.org/0000-0002-9501-3757</orcidid></addata></record> |
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| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2021-07, Vol.40 (30), p.4941-4953 |
| issn | 0950-9232 1476-5594 1476-5594 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2544882100 |
| source | MEDLINE; Alma/SFX Local Collection |
| subjects | 13/1 13/105 13/109 13/89 13/95 38/77 38/91 631/1647/514 631/67/1504/1329 64/110 692/53/2422 Animal models Apoptosis Autocrine Communication Autocrine mechanisms Autocrine signalling Bile Bile acids Biomarkers Biomarkers, Tumor Cancer Cell Biology Cell culture Cell Line Cell Proliferation Cellular signal transduction Cyclic adenylic acid Cyclic AMP Cyclic AMP - metabolism Development and progression Disease Progression Disease Susceptibility Early Growth Response Protein 1 - metabolism EGR-1 protein Fibroblast growth factor receptor 1 Fibroblast growth factor receptor 4 Fibroblast growth factor receptors Fibroblast growth factors Fibroblast Growth Factors - metabolism Fibroblasts Gallbladder Gallbladder cancer Gallbladder Neoplasms - etiology Gallbladder Neoplasms - metabolism Gallbladder Neoplasms - mortality Gallbladder Neoplasms - pathology Gene Expression Regulation, Neoplastic Genetic aspects Growth factor receptors Health aspects Human Genetics Humans Internal Medicine Medicine Medicine & Public Health Oncology Oncology, Experimental Patients Prognosis Protein Binding Protein kinases Receptor, Fibroblast Growth Factor, Type 4 - metabolism Receptors, G-Protein-Coupled - metabolism RNA, Messenger Signal Transduction Transcription Transcription factors |
| title | FGF19 and FGFR4 promotes the progression of gallbladder carcinoma in an autocrine pathway dependent on GPBAR1-cAMP-EGR1 axis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-26T00%3A29%3A32IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=FGF19%20and%20FGFR4%20promotes%20the%20progression%20of%20gallbladder%20carcinoma%20in%20an%20autocrine%20pathway%20dependent%20on%20GPBAR1-cAMP-EGR1%20axis&rft.jtitle=Oncogene&rft.au=Chen,%20Tianli&rft.date=2021-07-29&rft.volume=40&rft.issue=30&rft.spage=4941&rft.epage=4953&rft.pages=4941-4953&rft.issn=0950-9232&rft.eissn=1476-5594&rft_id=info:doi/10.1038/s41388-021-01850-1&rft_dat=%3Cgale_proqu%3EA670042473%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2556149386&rft_id=info:pmid/34163030&rft_galeid=A670042473&rfr_iscdi=true |