The extracellular matrix protein type I collagen and fibronectin are regulated by β-arrestin-1/endothelin axis in human ovarian fibroblasts

间质细胞 细胞外基质 纤维连接蛋白 生物 癌症研究 胶原受体 卵巢癌 成纤维细胞 分子生物学 细胞生物学 骨膜炎 化学 细胞粘附 细胞培养 细胞 癌症 遗传学
作者
Ilenia Masi,Flavia Ottavi,Valentina Caprara,Danila Del Rio,Martina Kunkl,Francesca Spadaro,Valerio Licursi,Loretta Tuosto,Anna Bagnato,Laura Rosanò
出处
期刊:Journal of Experimental & Clinical Cancer Research [BioMed Central]
卷期号:44 (1)
标识
DOI:10.1186/s13046-025-03327-5
摘要

Abstract Background The invasive and metastatic spread of serous ovarian cancer (SOC) results from the cooperative interactions between cancer and stroma, which include extracellular matrix (ECM) and cellular components, including cancer-associated fibroblasts (CAFs). Soluble factors secreted by cancer and stromal cells contribute to stroma remodeling through the secretion of ECM proteins, providing a favorable environment for cancer cell dissemination. The peptide endothelin-1 (ET-1), through two G protein-coupled receptors (GPCR), endothelin receptor type A (ET A R) and B (ET B R), acts on both cancer and stromal cells, engaging the protein β-arrestin1 (β-arr1), to bolster SOC progression. However, its role in the regulation of the ECM proteins by ovarian fibroblasts is not understood. This study delves into the role of ET-1 as a regulator of type I collagen (Col1) and fibronectin (FN). Methods We used human primary ovarian fibroblasts (HOFs) and CAFs. The expression of Col1 ( COL1A1 ) and FN ( FN1 ) were detected by western blotting (WB), quantitative real time-polymerase chain reaction (qRT-PCR), immunofluorescence (IF), and confocal laser scanning microscopy (CLSM) in cells and tumor tissue sections from mice xenografts, while the transcription of COL1A1 was detected by luciferase reporter gene assay. The nuclear function of β-arr1 was evaluated by silencing and rescue expression with wild-type (WT) and nuclear mutant plasmid constructs, RNA seq and differential gene expression and gene sets enrichment analyses. The prognostic role of COL1A1 , FN1 , EDN1 (ET-1) and ARRB1 (β-arr1) gene expression was evaluated using the Kaplan–Meier plotter database and clinical ovarian cancer tissue samples. Results We demonstrated that ET-1 boosts Col1 and FN expression in HOFs, akin to ovarian CAF levels. Both receptors are implicated, evident from inhibitory effects after ET A R or ET B R antagonist treatments and notably with bosentan, a dual antagonist, in vitro and in vivo. At the molecular level, ET-1 triggers the activation of COL1A1 promoter activity and its enhanced expression via β-arr1 nuclear function. Transcriptome analysis of β-arr1-silenced HOFs confirms the nuclear role of β-arr1 in collagen and ECM remodeling-related protein transcriptional regulation. Accordingly, a high level of EDN1/ARRB1 expression in combination with either COL1A1 or FN1 is associated with the poor prognosis of SOC patients. Conclusions These findings hint at ET-1 involvement in ECM remodeling and early SOC stages by modulating the expression of Col1 and FN. Targeting ET-1 signaling with ET A R/ET B R antagonists might interfere with the ability of CAFs to produce key ECM proteins in this tumor.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
脑洞疼应助暴躁小龙采纳,获得10
刚刚
笑点低方盒完成签到,获得积分10
1秒前
归尘发布了新的文献求助10
1秒前
传奇3应助momo采纳,获得10
1秒前
2秒前
胡图图发布了新的文献求助10
3秒前
5秒前
蜜HHH完成签到 ,获得积分10
6秒前
7秒前
7秒前
我要文献发布了新的文献求助10
8秒前
8秒前
8秒前
量子星尘发布了新的文献求助10
11秒前
暴躁小龙发布了新的文献求助10
12秒前
张润泽完成签到 ,获得积分10
12秒前
13秒前
文档发布了新的文献求助10
13秒前
14秒前
16秒前
17秒前
17秒前
18秒前
19秒前
19秒前
烟花应助zwk采纳,获得10
21秒前
蔡芝艳关注了科研通微信公众号
21秒前
YI完成签到,获得积分10
24秒前
24秒前
大个应助科研通管家采纳,获得10
25秒前
25秒前
充电宝应助科研通管家采纳,获得10
26秒前
SYLH应助科研通管家采纳,获得20
26秒前
Ava应助科研通管家采纳,获得10
26秒前
丘比特应助科研通管家采纳,获得10
26秒前
情怀应助科研通管家采纳,获得10
26秒前
Hello应助科研通管家采纳,获得10
26秒前
Owen应助科研通管家采纳,获得10
26秒前
26秒前
su发布了新的文献求助10
28秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989297
求助须知:如何正确求助?哪些是违规求助? 3531418
关于积分的说明 11253893
捐赠科研通 3270097
什么是DOI,文献DOI怎么找? 1804884
邀请新用户注册赠送积分活动 882087
科研通“疑难数据库(出版商)”最低求助积分说明 809158