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。

IF 4.2 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY
Gastroenterology Report Pub Date : 2025-10-01 eCollection Date: 2025-01-01 DOI:10.1093/gastro/goaf090
Xin Wang, Guoli Sheng, Zhangdi Yan, Anda Shi, Zengli Liu, Yongchang Tang, Guangzhen Li, Zongli Zhang
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引用次数: 0

摘要

背景:本研究旨在确定组胺(HA)-组胺受体H2 (HRH2)信号通路对肿瘤相关成纤维细胞(CAFs)分泌肝细胞生长因子(HGF)的影响,并阐明HGF促进胆管癌进展的机制。此外,我们的研究已经确定了新的靶点,并研究了西咪替丁和卡马替尼在胆管癌中的潜在应用。方法:单细胞RNA测序结果显示,HRH2和HGF在cas中的表达存在显著相关性。体外/体内实验显示,HA可通过上调转录因子缺氧诱导因子1亚单位α (hypoxia inducible factor 1 subunit α, HIF-1α)促进HGF的转录。通过原位模型和体外实验证实HGF促进胆管癌的进展。结果:在胆管癌肿瘤微环境中,HRH2和HGF主要在cas中表达。来自肥大细胞的HA可以与caf上的HRH2受体结合,从而上调HIF-1α,从而提高HGF的转录和分泌水平。HGF上调胆管癌细胞内FOS-like 1 (FOSL1)的磷酸化,促进基质金属肽酶10 (MMP10)的表达,从而增强胆管癌细胞的侵袭和迁移能力。结论:HA-HRH2信号通路介导caf中HGF的增殖和分泌。HIF-1α和FOSL1在驱动胆管癌细胞在肿瘤微环境中的增殖、侵袭和迁移中发挥了至关重要的作用。此外,本研究为HA受体HRH2抑制剂西咪替丁和HGF受体细胞间充质上皮转化因子(c-MET)抑制剂卡马替尼在胆道肿瘤中的应用提供了理论支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
Gastroenterology Report
Gastroenterology Report Medicine-Gastroenterology
CiteScore
4.60
自引率
2.80%
发文量
63
审稿时长
8 weeks
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.
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