VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression via a novel autocrine mechanism
Although VPAC1 and its ligand vasoactive intestinal peptide (VIP) are important in gastrointestinal physiology, their involvements in progression of gastrointestinal tumor have not been explored. Here, we found that higher expression of VIP/VPAC1 was observed in gastric cancer compared to the adjace...
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| Veröffentlicht in: | Oncogene 2019-05, Vol.38 (20), p.3946-3961 |
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| creator | Tang, Bo Wu, Jilin Zhu, Michael X. Sun, Xuemei Liu, Jingjing Xie, Rui Dong, Tobias Xiao Xiao, Yufeng Carethers, John M. Yang, Shiming Dong, Hui |
| description | Although VPAC1 and its ligand vasoactive intestinal peptide (VIP) are important in gastrointestinal physiology, their involvements in progression of gastrointestinal tumor have not been explored. Here, we found that higher expression of VIP/VPAC1 was observed in gastric cancer compared to the adjacent normal tissues. The increased expression of VIP/VPAC1 in gastric cancer correlated positively with invasion, tumor stage, lymph node, distant metastases, and poor survival. Moreover, high expression of VIP and VPAC1, advanced tumor stage and distant metastasis were independent prognostic factors. VPAC1 activation by VIP markedly induced TRPV4-mediated Ca
2+
entry, and eventually promoted gastric cancer progression in a Ca
2+
signaling-dependent manner. Inhibition of VPAC1 and its signaling pathway could block the progressive responses. VPAC1/TRPV4/Ca
2+
signaling in turn enhanced the expression and secretion of VIP in gastric cancer cells, enforcing a positive feedback regulation mechanism. Taken together, our study demonstrate that VPAC1 is significantly overexpressed in gastric cancer and VPAC1/TRPV4/Ca
2+
signaling axis could enforce a positive feedback regulation in gastric cancer progression. VIP/VPAC1 may serve as potential prognostic markers and therapeutic targets for gastric cancer. |
| doi_str_mv | 10.1038/s41388-019-0709-6 |
| format | Article |
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2+
entry, and eventually promoted gastric cancer progression in a Ca
2+
signaling-dependent manner. Inhibition of VPAC1 and its signaling pathway could block the progressive responses. VPAC1/TRPV4/Ca
2+
signaling in turn enhanced the expression and secretion of VIP in gastric cancer cells, enforcing a positive feedback regulation mechanism. Taken together, our study demonstrate that VPAC1 is significantly overexpressed in gastric cancer and VPAC1/TRPV4/Ca
2+
signaling axis could enforce a positive feedback regulation in gastric cancer progression. VIP/VPAC1 may serve as potential prognostic markers and therapeutic targets for gastric cancer.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-019-0709-6</identifier><identifier>PMID: 30692637</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/105 ; 13/51 ; 14/19 ; 45/77 ; 45/90 ; 631/67/1504/1829 ; 631/80/86/1999 ; 64/60 ; 82/80 ; 9/74 ; 96/95 ; Animals ; Apoptosis ; Autocrine signalling ; Calcium - metabolism ; Calcium influx ; Calcium signalling ; Cancer ; Cancer cells ; Cancer metastasis ; Cancer research ; Cell Biology ; Cell Line, Tumor ; Cell Movement ; Development and progression ; Feedback ; Gastric cancer ; Gastrointestinal diseases ; Gene expression ; Genetic aspects ; Human Genetics ; Humans ; Internal Medicine ; Intestine ; Kaplan-Meier Estimate ; Lung Neoplasms - secondary ; Lymph nodes ; Male ; Medical prognosis ; Medical research ; Medical schools ; Medicine ; Medicine & Public Health ; Metastases ; Mice, Inbred BALB C ; Oncology ; Peptides ; Receptors, Vasoactive Intestinal Polypeptide, Type I - genetics ; Receptors, Vasoactive Intestinal Polypeptide, Type I - metabolism ; Secretion ; Signal transduction ; Stomach cancer ; Stomach Neoplasms - metabolism ; Stomach Neoplasms - mortality ; Stomach Neoplasms - pathology ; Therapeutic applications ; TRPV Cation Channels - genetics ; TRPV Cation Channels - metabolism ; Tumors ; Vasoactive agents ; Vasoactive intestinal peptide ; Vasoactive Intestinal Peptide - metabolism ; Vasoactive intestinal peptides ; Xenograft Model Antitumor Assays</subject><ispartof>Oncogene, 2019-05, Vol.38 (20), p.3946-3961</ispartof><rights>Springer Nature Limited 2019</rights><rights>COPYRIGHT 2019 Nature Publishing Group</rights><rights>2019© Springer Nature Limited 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c482t-f8adf0aaaab51953214b9ca3016eab3a550770762af8a552b84f7a7e1ab38df03</citedby><cites>FETCH-LOGICAL-c482t-f8adf0aaaab51953214b9ca3016eab3a550770762af8a552b84f7a7e1ab38df03</cites><orcidid>0000-0001-5500-7099</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41388-019-0709-6$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41388-019-0709-6$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30692637$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tang, Bo</creatorcontrib><creatorcontrib>Wu, Jilin</creatorcontrib><creatorcontrib>Zhu, Michael X.</creatorcontrib><creatorcontrib>Sun, Xuemei</creatorcontrib><creatorcontrib>Liu, Jingjing</creatorcontrib><creatorcontrib>Xie, Rui</creatorcontrib><creatorcontrib>Dong, Tobias Xiao</creatorcontrib><creatorcontrib>Xiao, Yufeng</creatorcontrib><creatorcontrib>Carethers, John M.</creatorcontrib><creatorcontrib>Yang, Shiming</creatorcontrib><creatorcontrib>Dong, Hui</creatorcontrib><title>VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression via a novel autocrine mechanism</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Although VPAC1 and its ligand vasoactive intestinal peptide (VIP) are important in gastrointestinal physiology, their involvements in progression of gastrointestinal tumor have not been explored. Here, we found that higher expression of VIP/VPAC1 was observed in gastric cancer compared to the adjacent normal tissues. The increased expression of VIP/VPAC1 in gastric cancer correlated positively with invasion, tumor stage, lymph node, distant metastases, and poor survival. Moreover, high expression of VIP and VPAC1, advanced tumor stage and distant metastasis were independent prognostic factors. VPAC1 activation by VIP markedly induced TRPV4-mediated Ca
2+
entry, and eventually promoted gastric cancer progression in a Ca
2+
signaling-dependent manner. Inhibition of VPAC1 and its signaling pathway could block the progressive responses. VPAC1/TRPV4/Ca
2+
signaling in turn enhanced the expression and secretion of VIP in gastric cancer cells, enforcing a positive feedback regulation mechanism. Taken together, our study demonstrate that VPAC1 is significantly overexpressed in gastric cancer and VPAC1/TRPV4/Ca
2+
signaling axis could enforce a positive feedback regulation in gastric cancer progression. VIP/VPAC1 may serve as potential prognostic markers and therapeutic targets for gastric cancer.</description><subject>13/105</subject><subject>13/51</subject><subject>14/19</subject><subject>45/77</subject><subject>45/90</subject><subject>631/67/1504/1829</subject><subject>631/80/86/1999</subject><subject>64/60</subject><subject>82/80</subject><subject>9/74</subject><subject>96/95</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Autocrine signalling</subject><subject>Calcium - metabolism</subject><subject>Calcium influx</subject><subject>Calcium signalling</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>Cancer metastasis</subject><subject>Cancer research</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement</subject><subject>Development and progression</subject><subject>Feedback</subject><subject>Gastric cancer</subject><subject>Gastrointestinal diseases</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Intestine</subject><subject>Kaplan-Meier Estimate</subject><subject>Lung Neoplasms - secondary</subject><subject>Lymph nodes</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Medical schools</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastases</subject><subject>Mice, Inbred BALB C</subject><subject>Oncology</subject><subject>Peptides</subject><subject>Receptors, Vasoactive Intestinal Polypeptide, Type I - genetics</subject><subject>Receptors, Vasoactive Intestinal Polypeptide, Type I - metabolism</subject><subject>Secretion</subject><subject>Signal transduction</subject><subject>Stomach cancer</subject><subject>Stomach Neoplasms - metabolism</subject><subject>Stomach Neoplasms - mortality</subject><subject>Stomach Neoplasms - pathology</subject><subject>Therapeutic applications</subject><subject>TRPV Cation Channels - genetics</subject><subject>TRPV Cation Channels - metabolism</subject><subject>Tumors</subject><subject>Vasoactive agents</subject><subject>Vasoactive intestinal peptide</subject><subject>Vasoactive Intestinal Peptide - metabolism</subject><subject>Vasoactive intestinal peptides</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><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><recordid>eNp1kU1rFTEYhYMo9lr9AW4k4MbN1HxMvpaXS_2AgkVqtyGTeec2ZSa5JjNV_70ZbrUomiwCeZ9zOMlB6CUlZ5Rw_ba0lGvdEGoaoohp5CO0oa2SjRCmfYw2xAjSGMbZCXpWyi0hRBnCnqITTqRhkqsN-n59ud1R7NNyGKHgb2G-wVefL69b7G9cjDDiOeFDTlOaAXs3-rBMTQ8HiD3EGe9dmXPwdRI95BXcZyglpIjvgsMOx3RXPdwyJ59DBDzB6hvK9Bw9GdxY4MX9eYq-vDu_2n1oLj69_7jbXjS-1WxuBu36gbi6OkGN4Iy2nfGOEyrBddwJQZQiSjJXSSFYp9tBOQW0DnVV8lP05uhbs31doMx2CsXDOLoIaSmWUWVaWf-CVfT1X-htWnKs6SxjTLZMc8YfqL0bwYY4pDk7v5rardBCcU0FrdTZP6i6e5iCTxGGUO__ENCjwOdUSobBHnKYXP5hKbFr2_bYtq1t27VtK6vm1X3gpZug_634VW8F2BEodRT3kB9e9H_Xn44is_w</recordid><startdate>201905</startdate><enddate>201905</enddate><creator>Tang, Bo</creator><creator>Wu, Jilin</creator><creator>Zhu, Michael X.</creator><creator>Sun, Xuemei</creator><creator>Liu, Jingjing</creator><creator>Xie, Rui</creator><creator>Dong, Tobias Xiao</creator><creator>Xiao, Yufeng</creator><creator>Carethers, John M.</creator><creator>Yang, Shiming</creator><creator>Dong, Hui</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5500-7099</orcidid></search><sort><creationdate>201905</creationdate><title>VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression via a novel autocrine mechanism</title><author>Tang, Bo ; Wu, Jilin ; Zhu, Michael X. ; Sun, Xuemei ; Liu, Jingjing ; Xie, Rui ; Dong, Tobias Xiao ; Xiao, Yufeng ; Carethers, John M. ; Yang, Shiming ; Dong, Hui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c482t-f8adf0aaaab51953214b9ca3016eab3a550770762af8a552b84f7a7e1ab38df03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>13/105</topic><topic>13/51</topic><topic>14/19</topic><topic>45/77</topic><topic>45/90</topic><topic>631/67/1504/1829</topic><topic>631/80/86/1999</topic><topic>64/60</topic><topic>82/80</topic><topic>9/74</topic><topic>96/95</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Autocrine signalling</topic><topic>Calcium - metabolism</topic><topic>Calcium influx</topic><topic>Calcium signalling</topic><topic>Cancer</topic><topic>Cancer cells</topic><topic>Cancer metastasis</topic><topic>Cancer research</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement</topic><topic>Development and progression</topic><topic>Feedback</topic><topic>Gastric cancer</topic><topic>Gastrointestinal diseases</topic><topic>Gene expression</topic><topic>Genetic aspects</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Intestine</topic><topic>Kaplan-Meier Estimate</topic><topic>Lung Neoplasms - secondary</topic><topic>Lymph nodes</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Medical research</topic><topic>Medical schools</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastases</topic><topic>Mice, Inbred BALB C</topic><topic>Oncology</topic><topic>Peptides</topic><topic>Receptors, Vasoactive Intestinal Polypeptide, Type I - genetics</topic><topic>Receptors, Vasoactive Intestinal Polypeptide, Type I - metabolism</topic><topic>Secretion</topic><topic>Signal transduction</topic><topic>Stomach cancer</topic><topic>Stomach Neoplasms - metabolism</topic><topic>Stomach Neoplasms - mortality</topic><topic>Stomach Neoplasms - pathology</topic><topic>Therapeutic applications</topic><topic>TRPV Cation Channels - genetics</topic><topic>TRPV Cation Channels - metabolism</topic><topic>Tumors</topic><topic>Vasoactive agents</topic><topic>Vasoactive intestinal peptide</topic><topic>Vasoactive Intestinal Peptide - metabolism</topic><topic>Vasoactive intestinal peptides</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tang, Bo</creatorcontrib><creatorcontrib>Wu, Jilin</creatorcontrib><creatorcontrib>Zhu, Michael X.</creatorcontrib><creatorcontrib>Sun, Xuemei</creatorcontrib><creatorcontrib>Liu, Jingjing</creatorcontrib><creatorcontrib>Xie, Rui</creatorcontrib><creatorcontrib>Dong, Tobias Xiao</creatorcontrib><creatorcontrib>Xiao, Yufeng</creatorcontrib><creatorcontrib>Carethers, John M.</creatorcontrib><creatorcontrib>Yang, Shiming</creatorcontrib><creatorcontrib>Dong, Hui</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>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</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>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tang, Bo</au><au>Wu, Jilin</au><au>Zhu, Michael X.</au><au>Sun, Xuemei</au><au>Liu, Jingjing</au><au>Xie, Rui</au><au>Dong, Tobias Xiao</au><au>Xiao, Yufeng</au><au>Carethers, John M.</au><au>Yang, Shiming</au><au>Dong, Hui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression via a novel autocrine mechanism</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2019-05</date><risdate>2019</risdate><volume>38</volume><issue>20</issue><spage>3946</spage><epage>3961</epage><pages>3946-3961</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Although VPAC1 and its ligand vasoactive intestinal peptide (VIP) are important in gastrointestinal physiology, their involvements in progression of gastrointestinal tumor have not been explored. Here, we found that higher expression of VIP/VPAC1 was observed in gastric cancer compared to the adjacent normal tissues. The increased expression of VIP/VPAC1 in gastric cancer correlated positively with invasion, tumor stage, lymph node, distant metastases, and poor survival. Moreover, high expression of VIP and VPAC1, advanced tumor stage and distant metastasis were independent prognostic factors. VPAC1 activation by VIP markedly induced TRPV4-mediated Ca
2+
entry, and eventually promoted gastric cancer progression in a Ca
2+
signaling-dependent manner. Inhibition of VPAC1 and its signaling pathway could block the progressive responses. VPAC1/TRPV4/Ca
2+
signaling in turn enhanced the expression and secretion of VIP in gastric cancer cells, enforcing a positive feedback regulation mechanism. Taken together, our study demonstrate that VPAC1 is significantly overexpressed in gastric cancer and VPAC1/TRPV4/Ca
2+
signaling axis could enforce a positive feedback regulation in gastric cancer progression. VIP/VPAC1 may serve as potential prognostic markers and therapeutic targets for gastric cancer.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30692637</pmid><doi>10.1038/s41388-019-0709-6</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0001-5500-7099</orcidid><oa>free_for_read</oa></addata></record> |
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| issn | 0950-9232 1476-5594 |
| language | eng |
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| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | 13/105 13/51 14/19 45/77 45/90 631/67/1504/1829 631/80/86/1999 64/60 82/80 9/74 96/95 Animals Apoptosis Autocrine signalling Calcium - metabolism Calcium influx Calcium signalling Cancer Cancer cells Cancer metastasis Cancer research Cell Biology Cell Line, Tumor Cell Movement Development and progression Feedback Gastric cancer Gastrointestinal diseases Gene expression Genetic aspects Human Genetics Humans Internal Medicine Intestine Kaplan-Meier Estimate Lung Neoplasms - secondary Lymph nodes Male Medical prognosis Medical research Medical schools Medicine Medicine & Public Health Metastases Mice, Inbred BALB C Oncology Peptides Receptors, Vasoactive Intestinal Polypeptide, Type I - genetics Receptors, Vasoactive Intestinal Polypeptide, Type I - metabolism Secretion Signal transduction Stomach cancer Stomach Neoplasms - metabolism Stomach Neoplasms - mortality Stomach Neoplasms - pathology Therapeutic applications TRPV Cation Channels - genetics TRPV Cation Channels - metabolism Tumors Vasoactive agents Vasoactive intestinal peptide Vasoactive Intestinal Peptide - metabolism Vasoactive intestinal peptides Xenograft Model Antitumor Assays |
| title | VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression via a novel autocrine mechanism |
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