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.
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