CRH promotes human colon cancer cell proliferation via IL‐6/JAK2/STAT3 signaling pathway and VEGF‐induced tumor angiogenesis
Corticotrophin‐releasing hormone (CRH) has been demonstrated to participate in various diseases. Our previous study showed that its receptor CRHR1 mediated the development of colitis‐associated cancer in mouse model. However, the detailed mechanisms remain unclear. In this study, we explored the onc...
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| Veröffentlicht in: | Molecular carcinogenesis 2017-11, Vol.56 (11), p.2434-2445 |
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| creator | Fang, Xianjun Hong, Yali Dai, Li Qian, Yuanyuan Zhu, Chao Wu, Biao Li, Shengnan |
| description | Corticotrophin‐releasing hormone (CRH) has been demonstrated to participate in various diseases. Our previous study showed that its receptor CRHR1 mediated the development of colitis‐associated cancer in mouse model. However, the detailed mechanisms remain unclear. In this study, we explored the oncogenetic role of CRH/CRHR1 signaling in colon cancer cells. Cell proliferation and colony formation assays revealed that CRH contributed to cell proliferation. Moreover, tube formation assay showed that CRH‐treated colon cancer cell supernatant significantly promoted tube formation of human umbilical vein endothelial cells (HUVECs). And these effects could be reversed by the CRHR1 specific antagonist Antalarmin. Further investigation showed that CRH significantly upregulated the expressions of interlukin‐6 (IL‐6) and vascular endothelial growth factor (VEGF) through activating nuclear factor‐kappa B (NF‐κB). The CRH‐induced IL‐6 promoted phosphorylation of janus kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3). STAT3 inhibition by Stattic significantly inhibited the CRH‐induced cell proliferation. In addition, silence of VEGF resulted in declined tube formation induced by CRH. Taken together, CRH/CRHR1 signaling promoted human colon cancer cell proliferation via NF‐κB/IL‐6/JAK2/STAT3 signaling pathway and tumor angiogenesis via NF‐κB/VEGF signaling pathway. Our results provide evidence to support a critical role for the CRH/CRHR1 signaling in colon cancer progression and suggest its potential utility as a new therapeutic target for colon cancer. |
| doi_str_mv | 10.1002/mc.22691 |
| format | Article |
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Our previous study showed that its receptor CRHR1 mediated the development of colitis‐associated cancer in mouse model. However, the detailed mechanisms remain unclear. In this study, we explored the oncogenetic role of CRH/CRHR1 signaling in colon cancer cells. Cell proliferation and colony formation assays revealed that CRH contributed to cell proliferation. Moreover, tube formation assay showed that CRH‐treated colon cancer cell supernatant significantly promoted tube formation of human umbilical vein endothelial cells (HUVECs). And these effects could be reversed by the CRHR1 specific antagonist Antalarmin. Further investigation showed that CRH significantly upregulated the expressions of interlukin‐6 (IL‐6) and vascular endothelial growth factor (VEGF) through activating nuclear factor‐kappa B (NF‐κB). The CRH‐induced IL‐6 promoted phosphorylation of janus kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3). STAT3 inhibition by Stattic significantly inhibited the CRH‐induced cell proliferation. In addition, silence of VEGF resulted in declined tube formation induced by CRH. Taken together, CRH/CRHR1 signaling promoted human colon cancer cell proliferation via NF‐κB/IL‐6/JAK2/STAT3 signaling pathway and tumor angiogenesis via NF‐κB/VEGF signaling pathway. Our results provide evidence to support a critical role for the CRH/CRHR1 signaling in colon cancer progression and suggest its potential utility as a new therapeutic target for colon cancer.</description><identifier>ISSN: 0899-1987</identifier><identifier>EISSN: 1098-2744</identifier><identifier>DOI: 10.1002/mc.22691</identifier><identifier>PMID: 28618089</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Angiogenesis ; Antalarmin ; Cell growth ; Cell Line, Tumor ; Cell Proliferation ; Colitis ; Colon - blood supply ; Colon - metabolism ; Colon - pathology ; Colon cancer ; Colonic Neoplasms - blood supply ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; Colorectal cancer ; Corticotropin-releasing hormone ; Corticotropin-Releasing Hormone - metabolism ; CRH ; CRHR1 ; Endothelial cells ; Human Umbilical Vein Endothelial Cells ; Humans ; Interleukin 6 ; Interleukin-6 - metabolism ; Janus kinase ; Janus kinase 2 ; Janus Kinase 2 - metabolism ; Neovascularization, Pathologic - metabolism ; Neovascularization, Pathologic - pathology ; NF-κB protein ; Phosphorylation ; Receptors, Corticotropin-Releasing Hormone - metabolism ; Rodents ; Signal Transduction ; Silence ; STAT3 ; Stat3 protein ; STAT3 Transcription Factor - metabolism ; Transcription factors ; Transducers ; Umbilical vein ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - metabolism</subject><ispartof>Molecular carcinogenesis, 2017-11, Vol.56 (11), p.2434-2445</ispartof><rights>2017 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4151-165841a2185b36fa8a326ec4e0e115da6d7c72bb5d440946e9ffd6b17add369f3</citedby><cites>FETCH-LOGICAL-c4151-165841a2185b36fa8a326ec4e0e115da6d7c72bb5d440946e9ffd6b17add369f3</cites><orcidid>0000-0003-3764-7847</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fmc.22691$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fmc.22691$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28618089$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fang, Xianjun</creatorcontrib><creatorcontrib>Hong, Yali</creatorcontrib><creatorcontrib>Dai, Li</creatorcontrib><creatorcontrib>Qian, Yuanyuan</creatorcontrib><creatorcontrib>Zhu, Chao</creatorcontrib><creatorcontrib>Wu, Biao</creatorcontrib><creatorcontrib>Li, Shengnan</creatorcontrib><title>CRH promotes human colon cancer cell proliferation via IL‐6/JAK2/STAT3 signaling pathway and VEGF‐induced tumor angiogenesis</title><title>Molecular carcinogenesis</title><addtitle>Mol Carcinog</addtitle><description>Corticotrophin‐releasing hormone (CRH) has been demonstrated to participate in various diseases. Our previous study showed that its receptor CRHR1 mediated the development of colitis‐associated cancer in mouse model. However, the detailed mechanisms remain unclear. In this study, we explored the oncogenetic role of CRH/CRHR1 signaling in colon cancer cells. Cell proliferation and colony formation assays revealed that CRH contributed to cell proliferation. Moreover, tube formation assay showed that CRH‐treated colon cancer cell supernatant significantly promoted tube formation of human umbilical vein endothelial cells (HUVECs). And these effects could be reversed by the CRHR1 specific antagonist Antalarmin. Further investigation showed that CRH significantly upregulated the expressions of interlukin‐6 (IL‐6) and vascular endothelial growth factor (VEGF) through activating nuclear factor‐kappa B (NF‐κB). The CRH‐induced IL‐6 promoted phosphorylation of janus kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3). STAT3 inhibition by Stattic significantly inhibited the CRH‐induced cell proliferation. In addition, silence of VEGF resulted in declined tube formation induced by CRH. Taken together, CRH/CRHR1 signaling promoted human colon cancer cell proliferation via NF‐κB/IL‐6/JAK2/STAT3 signaling pathway and tumor angiogenesis via NF‐κB/VEGF signaling pathway. Our results provide evidence to support a critical role for the CRH/CRHR1 signaling in colon cancer progression and suggest its potential utility as a new therapeutic target for colon cancer.</description><subject>Angiogenesis</subject><subject>Antalarmin</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Colitis</subject><subject>Colon - blood supply</subject><subject>Colon - metabolism</subject><subject>Colon - pathology</subject><subject>Colon cancer</subject><subject>Colonic Neoplasms - blood supply</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - pathology</subject><subject>Colorectal cancer</subject><subject>Corticotropin-releasing hormone</subject><subject>Corticotropin-Releasing Hormone - metabolism</subject><subject>CRH</subject><subject>CRHR1</subject><subject>Endothelial cells</subject><subject>Human Umbilical Vein Endothelial Cells</subject><subject>Humans</subject><subject>Interleukin 6</subject><subject>Interleukin-6 - metabolism</subject><subject>Janus kinase</subject><subject>Janus kinase 2</subject><subject>Janus Kinase 2 - metabolism</subject><subject>Neovascularization, Pathologic - metabolism</subject><subject>Neovascularization, Pathologic - pathology</subject><subject>NF-κB protein</subject><subject>Phosphorylation</subject><subject>Receptors, Corticotropin-Releasing Hormone - metabolism</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Silence</subject><subject>STAT3</subject><subject>Stat3 protein</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Transcription factors</subject><subject>Transducers</subject><subject>Umbilical vein</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><issn>0899-1987</issn><issn>1098-2744</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1q3DAUhUVoaSZpIU9QBNl044yuLMvSchjy104JpJNsjSzJEwXbmkh2w-zyCHnGPkk1nSSFQjf3Ls7HB4eD0BGQEyCETjt9QimXsIcmQKTIaMnYOzQhQsoMpCj30UGM94QAlAX5gPap4CBSOkFP8-sLvA6-84ON-G7sVI-1b326qtc2YG3bdgu0rrFBDS4lP53Cl4tfT898-nX2jU5_LGfLHEe36lXr-hVeq-HuUW2w6g2-PT0_S6TrzaitwcPY-ZCClfMr29vo4kf0vlFttJ9e_iG6OTtdzi-yxdX55Xy2yDSDAjLghWCgKIiiznmjhMopt5pZYgEKo7gpdUnrujCMEcm4lU1jeA2lMibnsskP0ZedN3V5GG0cqs7FbTnVWz_GCiSQUrK8ZAk9_ge992NI5bYUEzmVoiB_hTr4GINtqnVwnQqbCki1XaXqdPVnlYR-fhGOdWfNG_g6QwKyHfDoWrv5r6j6Pt8JfwN6n5Y6</recordid><startdate>201711</startdate><enddate>201711</enddate><creator>Fang, Xianjun</creator><creator>Hong, Yali</creator><creator>Dai, Li</creator><creator>Qian, Yuanyuan</creator><creator>Zhu, Chao</creator><creator>Wu, Biao</creator><creator>Li, Shengnan</creator><general>Wiley Subscription Services, Inc</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>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3764-7847</orcidid></search><sort><creationdate>201711</creationdate><title>CRH promotes human colon cancer cell proliferation via IL‐6/JAK2/STAT3 signaling pathway and VEGF‐induced tumor angiogenesis</title><author>Fang, Xianjun ; Hong, Yali ; Dai, Li ; Qian, Yuanyuan ; Zhu, Chao ; Wu, Biao ; Li, Shengnan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4151-165841a2185b36fa8a326ec4e0e115da6d7c72bb5d440946e9ffd6b17add369f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Angiogenesis</topic><topic>Antalarmin</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Colitis</topic><topic>Colon - blood supply</topic><topic>Colon - metabolism</topic><topic>Colon - pathology</topic><topic>Colon cancer</topic><topic>Colonic Neoplasms - blood supply</topic><topic>Colonic Neoplasms - metabolism</topic><topic>Colonic Neoplasms - pathology</topic><topic>Colorectal cancer</topic><topic>Corticotropin-releasing hormone</topic><topic>Corticotropin-Releasing Hormone - metabolism</topic><topic>CRH</topic><topic>CRHR1</topic><topic>Endothelial cells</topic><topic>Human Umbilical Vein Endothelial Cells</topic><topic>Humans</topic><topic>Interleukin 6</topic><topic>Interleukin-6 - metabolism</topic><topic>Janus kinase</topic><topic>Janus kinase 2</topic><topic>Janus Kinase 2 - metabolism</topic><topic>Neovascularization, Pathologic - metabolism</topic><topic>Neovascularization, Pathologic - pathology</topic><topic>NF-κB protein</topic><topic>Phosphorylation</topic><topic>Receptors, Corticotropin-Releasing Hormone - metabolism</topic><topic>Rodents</topic><topic>Signal Transduction</topic><topic>Silence</topic><topic>STAT3</topic><topic>Stat3 protein</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Transcription factors</topic><topic>Transducers</topic><topic>Umbilical vein</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fang, Xianjun</creatorcontrib><creatorcontrib>Hong, Yali</creatorcontrib><creatorcontrib>Dai, Li</creatorcontrib><creatorcontrib>Qian, Yuanyuan</creatorcontrib><creatorcontrib>Zhu, Chao</creatorcontrib><creatorcontrib>Wu, Biao</creatorcontrib><creatorcontrib>Li, Shengnan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular carcinogenesis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fang, Xianjun</au><au>Hong, Yali</au><au>Dai, Li</au><au>Qian, Yuanyuan</au><au>Zhu, Chao</au><au>Wu, Biao</au><au>Li, Shengnan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CRH promotes human colon cancer cell proliferation via IL‐6/JAK2/STAT3 signaling pathway and VEGF‐induced tumor angiogenesis</atitle><jtitle>Molecular carcinogenesis</jtitle><addtitle>Mol Carcinog</addtitle><date>2017-11</date><risdate>2017</risdate><volume>56</volume><issue>11</issue><spage>2434</spage><epage>2445</epage><pages>2434-2445</pages><issn>0899-1987</issn><eissn>1098-2744</eissn><abstract>Corticotrophin‐releasing hormone (CRH) has been demonstrated to participate in various diseases. Our previous study showed that its receptor CRHR1 mediated the development of colitis‐associated cancer in mouse model. However, the detailed mechanisms remain unclear. In this study, we explored the oncogenetic role of CRH/CRHR1 signaling in colon cancer cells. Cell proliferation and colony formation assays revealed that CRH contributed to cell proliferation. Moreover, tube formation assay showed that CRH‐treated colon cancer cell supernatant significantly promoted tube formation of human umbilical vein endothelial cells (HUVECs). And these effects could be reversed by the CRHR1 specific antagonist Antalarmin. Further investigation showed that CRH significantly upregulated the expressions of interlukin‐6 (IL‐6) and vascular endothelial growth factor (VEGF) through activating nuclear factor‐kappa B (NF‐κB). The CRH‐induced IL‐6 promoted phosphorylation of janus kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3). STAT3 inhibition by Stattic significantly inhibited the CRH‐induced cell proliferation. In addition, silence of VEGF resulted in declined tube formation induced by CRH. Taken together, CRH/CRHR1 signaling promoted human colon cancer cell proliferation via NF‐κB/IL‐6/JAK2/STAT3 signaling pathway and tumor angiogenesis via NF‐κB/VEGF signaling pathway. Our results provide evidence to support a critical role for the CRH/CRHR1 signaling in colon cancer progression and suggest its potential utility as a new therapeutic target for colon cancer.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>28618089</pmid><doi>10.1002/mc.22691</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-3764-7847</orcidid></addata></record> |
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| subjects | Angiogenesis Antalarmin Cell growth Cell Line, Tumor Cell Proliferation Colitis Colon - blood supply Colon - metabolism Colon - pathology Colon cancer Colonic Neoplasms - blood supply Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Colorectal cancer Corticotropin-releasing hormone Corticotropin-Releasing Hormone - metabolism CRH CRHR1 Endothelial cells Human Umbilical Vein Endothelial Cells Humans Interleukin 6 Interleukin-6 - metabolism Janus kinase Janus kinase 2 Janus Kinase 2 - metabolism Neovascularization, Pathologic - metabolism Neovascularization, Pathologic - pathology NF-κB protein Phosphorylation Receptors, Corticotropin-Releasing Hormone - metabolism Rodents Signal Transduction Silence STAT3 Stat3 protein STAT3 Transcription Factor - metabolism Transcription factors Transducers Umbilical vein Vascular endothelial growth factor Vascular Endothelial Growth Factor A - metabolism |
| title | CRH promotes human colon cancer cell proliferation via IL‐6/JAK2/STAT3 signaling pathway and VEGF‐induced tumor angiogenesis |
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