{"title":"组胺驱动的癌相关成纤维细胞和肝细胞生长因子在胆管癌进展中的作用。","authors":"Xin Wang, Guoli Sheng, Zhangdi Yan, Anda Shi, Zengli Liu, Yongchang Tang, Guangzhen Li, Zongli Zhang","doi":"10.1093/gastro/goaf090","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Here, we aimed to identify the impact of the histamine (HA)-histamine receptor H2 (HRH2) signaling pathway on stimulating the secretion of hepatocyte growth factor (HGF) by cancer-associated fibroblasts (CAFs), as well as elucidating the mechanisms through which HGF promotes the progression of cholangiocarcinoma. In addition, our study has identified novel targets and investigated the potential use of Cimetidine and Capmatinib in cholangiocarcinoma.</p><p><strong>Methods: </strong>Single-cell RNA sequencing revealed a noteworthy correlation between the expression of <i>HRH2</i> and <i>HGF</i> in CAFs. HA was able to promote the transcription of HGF through the upregulation of the transcription factor hypoxia inducible factor 1 subunit alpha (HIF-1α), which was revealed by using <i>in vitro</i>/<i>vivo</i> experiments. That HGF promotes the progression of cholangiocarcinoma was identified by using orthotopic models and <i>in vitro</i> experiments.</p><p><strong>Results: </strong>HRH2 and HGF were primarily expressed in CAFs within the tumor microenvironment of cholangiocarcinoma. HA sourced from mast cells could bind to the HRH2 receptor on CAFs, consequently upregulating HIF-1α and subsequently enhancing the transcription and secretion levels of HGF. HGF upregulates the phosphorylation of FOS-like 1 (FOSL1) within cholangiocarcinoma cells, promoting the expression of matrix metallopeptidase 10 (MMP10), and consequently enhancing the invasive and migratory abilities of cholangiocarcinoma cells.</p><p><strong>Conclusions: </strong>The HA-HRH2 signaling pathway mediates the proliferation and secretion of HGF in CAFs. HIF-1α and FOSL1 played crucial roles in driving the proliferation, invasion, and migration of cholangiocarcinoma cells within the tumor microenvironment, orchestrated by CAFs. Furthermore, this study has provided theoretical support for the application of the HA receptor HRH2 inhibitor, Cimetidine, and the HGF receptor cellular mesenchymal-epithelial transition factor (c-MET) inhibitor, Capmatinib, in biliary tract tumors.</p>","PeriodicalId":54275,"journal":{"name":"Gastroenterology Report","volume":"13 ","pages":"goaf090"},"PeriodicalIF":4.2000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12493034/pdf/","citationCount":"0","resultStr":"{\"title\":\"Function of histamine-driven cancer-associated fibroblast and hepatocyte growth factor in the progression of cholangiocarcinoma.\",\"authors\":\"Xin Wang, Guoli Sheng, Zhangdi Yan, Anda Shi, Zengli Liu, Yongchang Tang, Guangzhen Li, Zongli Zhang\",\"doi\":\"10.1093/gastro/goaf090\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Here, we aimed to identify the impact of the histamine (HA)-histamine receptor H2 (HRH2) signaling pathway on stimulating the secretion of hepatocyte growth factor (HGF) by cancer-associated fibroblasts (CAFs), as well as elucidating the mechanisms through which HGF promotes the progression of cholangiocarcinoma. In addition, our study has identified novel targets and investigated the potential use of Cimetidine and Capmatinib in cholangiocarcinoma.</p><p><strong>Methods: </strong>Single-cell RNA sequencing revealed a noteworthy correlation between the expression of <i>HRH2</i> and <i>HGF</i> in CAFs. HA was able to promote the transcription of HGF through the upregulation of the transcription factor hypoxia inducible factor 1 subunit alpha (HIF-1α), which was revealed by using <i>in vitro</i>/<i>vivo</i> experiments. That HGF promotes the progression of cholangiocarcinoma was identified by using orthotopic models and <i>in vitro</i> experiments.</p><p><strong>Results: </strong>HRH2 and HGF were primarily expressed in CAFs within the tumor microenvironment of cholangiocarcinoma. HA sourced from mast cells could bind to the HRH2 receptor on CAFs, consequently upregulating HIF-1α and subsequently enhancing the transcription and secretion levels of HGF. HGF upregulates the phosphorylation of FOS-like 1 (FOSL1) within cholangiocarcinoma cells, promoting the expression of matrix metallopeptidase 10 (MMP10), and consequently enhancing the invasive and migratory abilities of cholangiocarcinoma cells.</p><p><strong>Conclusions: </strong>The HA-HRH2 signaling pathway mediates the proliferation and secretion of HGF in CAFs. HIF-1α and FOSL1 played crucial roles in driving the proliferation, invasion, and migration of cholangiocarcinoma cells within the tumor microenvironment, orchestrated by CAFs. Furthermore, this study has provided theoretical support for the application of the HA receptor HRH2 inhibitor, Cimetidine, and the HGF receptor cellular mesenchymal-epithelial transition factor (c-MET) inhibitor, Capmatinib, in biliary tract tumors.</p>\",\"PeriodicalId\":54275,\"journal\":{\"name\":\"Gastroenterology Report\",\"volume\":\"13 \",\"pages\":\"goaf090\"},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2025-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12493034/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Gastroenterology Report\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/gastro/goaf090\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gastroenterology Report","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/gastro/goaf090","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
Function of histamine-driven cancer-associated fibroblast and hepatocyte growth factor in the progression of cholangiocarcinoma.
Background: Here, we aimed to identify the impact of the histamine (HA)-histamine receptor H2 (HRH2) signaling pathway on stimulating the secretion of hepatocyte growth factor (HGF) by cancer-associated fibroblasts (CAFs), as well as elucidating the mechanisms through which HGF promotes the progression of cholangiocarcinoma. In addition, our study has identified novel targets and investigated the potential use of Cimetidine and Capmatinib in cholangiocarcinoma.
Methods: Single-cell RNA sequencing revealed a noteworthy correlation between the expression of HRH2 and HGF in CAFs. HA was able to promote the transcription of HGF through the upregulation of the transcription factor hypoxia inducible factor 1 subunit alpha (HIF-1α), which was revealed by using in vitro/vivo experiments. That HGF promotes the progression of cholangiocarcinoma was identified by using orthotopic models and in vitro experiments.
Results: HRH2 and HGF were primarily expressed in CAFs within the tumor microenvironment of cholangiocarcinoma. HA sourced from mast cells could bind to the HRH2 receptor on CAFs, consequently upregulating HIF-1α and subsequently enhancing the transcription and secretion levels of HGF. HGF upregulates the phosphorylation of FOS-like 1 (FOSL1) within cholangiocarcinoma cells, promoting the expression of matrix metallopeptidase 10 (MMP10), and consequently enhancing the invasive and migratory abilities of cholangiocarcinoma cells.
Conclusions: The HA-HRH2 signaling pathway mediates the proliferation and secretion of HGF in CAFs. HIF-1α and FOSL1 played crucial roles in driving the proliferation, invasion, and migration of cholangiocarcinoma cells within the tumor microenvironment, orchestrated by CAFs. Furthermore, this study has provided theoretical support for the application of the HA receptor HRH2 inhibitor, Cimetidine, and the HGF receptor cellular mesenchymal-epithelial transition factor (c-MET) inhibitor, Capmatinib, in biliary tract tumors.
期刊介绍:
Gastroenterology Report is an international fully open access (OA) online only journal, covering all areas related to gastrointestinal sciences, including studies of the alimentary tract, liver, biliary, pancreas, enteral nutrition and related fields. The journal aims to publish high quality research articles on both basic and clinical gastroenterology, authoritative reviews that bring together new advances in the field, as well as commentaries and highlight pieces that provide expert analysis of topical issues.