Extracellular matrix protein type I collagen and fibronectin are regulated by the endothelin axis in ovarian fibroblasts
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ABSTRACT:
PROVIDER: PRJNA1135959 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29828648_1.fastq.gz | Fastqsanger.gz | |||
| SRR29828648_2.fastq.gz | Fastqsanger.gz | |||
| SRR29828649_1.fastq.gz | Fastqsanger.gz | |||
| SRR29828649_2.fastq.gz | Fastqsanger.gz | |||
| SRR29828650_1.fastq.gz | Fastqsanger.gz |
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Project description:The invasive and metastatic spread of ovarian cancer (OC) results from the cooperative interactions between cancer and stroma, which include acellular extracellular matrix (ECM) and cellular components, such as cancer-associated fibroblasts (CAFs). Soluble growth factors secreted by cancer and stromal cells contribute to stroma remodeling through the synthesis and modification of ECM proteins, providing a favorable environment for cancer cell dissemination. Within the OC, the peptide endothelin-1 (ET-1), through two G protein-coupled receptors, ET A R and ET B R, supports tumor growth and progression by acting on both cancer and stromal cells. Many of these effects rely on the functional and molecular link with the protein b-arrestin1 (b-arr1). However, the precise role of ET-1 in regulating the expression of ECM proteins by primary human ovarian fibroblasts (HOFs) remains unclear. In this study, we aimed to elucidate the regulatory role of ET-1 in the expression of type I collagen (Col1) and fibronectin 1 (FN1). We report a significant increase in the expression of both Col1 and FN1 in cells stimulated with ET-1, both at mRNA and protein levels, reaching the amounts of proteins found in ovarian CAFs. The observed effects are associated with the activation of both receptors since they are impaired by treatment with either ET A R or ET B R antagonists in HOFs and CAFs. Furthermore, they are particularly affected by the dual ET A R/ET B R antagonist bosentan, in vitro and in vivo models. At the molecular level, ET-1 activates the Col1 promoter and enhances the expression of this gene through the nuclear function of β-arr1. The change in transcriptome of HOFs silenced for β-arr1 was analyzed to confirm the molecular response triggered by β-arr1, which resulted in the upregulation of ECM remodeling and collagen deposition. In summary, these findings demonstrate that the ET-1 axis may contribute to the remodeling of the ECM and probably to the early stages of OC progression by modulating the expression of Col1 and FN1. The targeting of ET-1 signaling with ET A R/ET B R antagonists may impede HOFs’ ability to produce key ECM proteins in this tumor.
2025-02-26 | GSE272256 | GEO
Project description:The goal of this study was to investigate the transcriptional regulation in cells grown on Fibronectin when compared to Collagen I 3 samples per condition
2016-07-04 | E-GEOD-81225 | biostudies-arrayexpress
Project description:The goal of this study was to investigate the transcriptional regulation in cells grown on Fibronectin when compared to Collagen I
2016-07-04 | GSE81225 | GEO
Project description:BackgroundThe 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 (ETAR) and B (ETBR), 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).MethodsWe 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.ResultsWe 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 ETAR or ETBR 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.ConclusionsThese 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 ETAR/ETBR antagonists might interfere with the ability of CAFs to produce key ECM proteins in this tumor.
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Project description:Collagen XII, belonging to the fibril-associated collagens, is a homotrimeric secreted extracellular matrix (ECM) protein encoded by the COL12A1 gene. Mutations in the human COL12A1 gene cause an Ehlers-Danlos/myopathy overlap syndrome leading to skeletal abnormalities and muscle weakness. Here, we studied the role of collagen XII in joint pathophysiology by analyzing collagen XII deficient mice and human patients. We found that collagen XII is widely expressed across multiple connective tissue of the developing joint. Lack of collagen XII in mice destabilizes tendons and the femoral trochlear groove to induce patellar subluxation in the patellofemoral joint. These changes are associated with an ECM damage response in tendon and secondary quadriceps muscle degeneration. Moreover, patellar subluxation was also identified as a clinical feature of human patients with collagen XII deficiency. The results provide an explanation for joint hyperlaxity in mice and human patients with collagen XII deficiency.
2023-06-19 | GSE234964 | GEO
Project description:Intestinal epithelial cells from the small intestine were seeded in either Matrigel or purified Type I Collagen in order to define the effect of matrix on cell fate.
2017-11-30 | E-MTAB-5247 | biostudies-arrayexpress
Project description:The intricate interplay between resident cells and the extracellular matrix (ECM) wields a profound influence on cancer progression. In Triple Negative Breast Cancer (TNBC), ECM architecture evolves primarily due to the enrichment of lysyl oxidase, fibronectin, and collagen that eventually promote distant metastasis. Here, we have uncovered a pivotal transcription regulatory mechanism of the epigenetic regulator UBR7 in conjunction with histone methyltransferase EZH2 in regulating TGF-b/Smad signalling-axis thereby fine-tuning the ECM genes. Remarkably, UBR7 loss leads to a dramatic reduction in the facultative heterochromatin mark H3K27me3 in chromatin, leading to ECM genes firing. Apart from playing a seminal role in matrix deposition in adherent-cancer cells and spheroids, UBR7 alters the total collagen content and lysyl oxidase activity thereby directly impacting the matrix stiffness and consequently its invasive properties. These results can be further translated to TNBC-patients, where reduced RNA/protein levels of UBR7 is accompanied by heightened expression of the ECM-components and their functional-activity which is responsible for fibrosis-mediated matrix stiffness. Thus, UBR7 acts as a master regulator of TNBC matrix-stiffening thereby impacting its metastatic potential.
2025-03-26 | GSE262488 | GEO
Project description:The intricate interplay between resident cells and the extracellular matrix (ECM) wields a profound influence on cancer progression. In Triple Negative Breast Cancer (TNBC), ECM architecture evolves primarily due to the enrichment of lysyl oxidase, fibronectin, and collagen that eventually promote distant metastasis. Here, we have uncovered a pivotal transcription regulatory mechanism of the epigenetic regulator UBR7 in conjunction with histone methyltransferase EZH2 in regulating TGF-b/Smad signalling-axis thereby fine-tuning the ECM genes. Remarkably, UBR7 loss leads to a dramatic reduction in the facultative heterochromatin mark H3K27me3 in chromatin, leading to ECM genes firing. Apart from playing a seminal role in matrix deposition in adherent-cancer cells and spheroids, UBR7 alters the total collagen content and lysyl oxidase activity thereby directly impacting the matrix stiffness and consequently its invasive properties. These results can be further translated to TNBC-patients, where reduced RNA/protein levels of UBR7 is accompanied by heightened expression of the ECM-components and their functional-activity which is responsible for fibrosis-mediated matrix stiffness. Thus, UBR7 acts as a master regulator of TNBC matrix-stiffening thereby impacting its metastatic potential.
2025-03-26 | GSE262487 | GEO
Project description:Ablation of collagen XII disturbs joint extracellular matrix organization and causes patellar subluxation
| PRJNA983815 | ENA
Project description:CD34+ hematopoietic stem/progenitor cells (HSC) reside in the bone marrow in close vicinity to the endosteal bone surface, surrounded by osteoblasts, stromal cells and various extracellular matrix molecules. We utilized a bioartificial matrix containing fibrillar collagen I, the major matrix component of bone, as scaffold for ex vivo expansion of HSCs. CD34+ HSCs were isolated from umbilical cord blood and cultivated within reconstituted collagen I fibrils in presence of FLT3-ligand, SCF and IL-3. After seven days of culture cell number, colony-forming units and gene expression profile of the cultured cells were assessed. Although the total expansion factor of CD34+ cells was slightly lower when cells were cultivated in the collagen I gel, the frequency of colony-forming units (CFU-C) increased compared to control suspension cultures. Gene expression analysis with microarray chip technology revealed the upregulation of more than 50 genes in presence of collagen I. Among them, genes for several growth factors, cytokines and chemokines (e.g. interleukin 8, MIP1-α) could be confirmed by quantitative PCR. Furthermore, increased expression of the negative cell-cycle regulator BTG2/TIS21 and an inhibitor of MAP kinase pathway, DUSP2, underline the regulatory role of the extracellular matrix. Together, these data show that the expansion of CD34+ cord blood cells in a culture system containing a three-dimensional collagen I matrix induces a qualitative change in the gene expression profile of cultivated HSCs. Keywords: hematopoietic stem/progenitor cells, collagen I, gene expression
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