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FOXP1 enhances fibrosis via activating Wnt/?-catenin signaling pathway in endometriosis.

ABSTRACT: Endometriosis is a common gynecological disorder affecting 6-10% women. Endometriosis is associated with excess fibrosis, leading to chronic pain, scarring and aberrant tissue function. However, molecular and cellular mechanisms underlying fibrosis during endometriosis still remain elusive. In this study we used endometrial and endometriotic stromal cells isolated from patients, and employed siRNA to knockdown Forkhead box protein P1 (FOXP1) to investigate the effect of FOXP1 on collagen contraction, cell proliferation and mitigation. Western blot and quantitative PCR were applied for analysis of protein and mRNA levels, respectively. Compared to control stromal cells, endometriotic stromal cells from patients exhibited higher levels of FOXP1 expression and Wnt-related ?-catenin acetylation. FOXP1 knockdown decreased not only Wnt signaling, but also the expression of fibrotic marker genes, including connective tissue growth factor, type I collagen, ?-smooth muscle actin and fibronectin. Furthermore, FOXP1 knockdown reversed the endometriotic cellular phenotypes, including reducing collagen gel contraction, inhibiting cell proliferation and migration. Finally, Wnt signaling inhibitor AVX939 blocked ?-catenin acetylation and endometrial stromal cell proliferation induced by ectopic FOXP1 expression. FOXP1 enhances fibrosis during endometriosis through upregulating Wnt signaling activity.

SUBMITTER: Shao X

PROVIDER: S-EPMC6291715 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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FOXP1 enhances fibrosis via activating Wnt/β-catenin signaling pathway in endometriosis.

Shao Xu X Wei Xin X

American journal of translational research 20181115 11

Endometriosis is a common gynecological disorder affecting 6-10% women. Endometriosis is associated with excess fibrosis, leading to chronic pain, scarring and aberrant tissue function. However, molecular and cellular mechanisms underlying fibrosis during endometriosis still remain elusive. In this study we used endometrial and endometriotic stromal cells isolated from patients, and employed siRNA to knockdown Forkhead box protein P1 (FOXP1) to investigate the effect of FOXP1 on collagen contrac ...[more]

PMID: 30662612

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Project description:BackgroundDuring the development and progression of endometriotic lesions, excess fibrosis may lead to scarring, chronic pain, and altered tissue function. However, the cellular and molecular mechanisms of fibrosis in endometriosis remain to be clarified.ObjectivesThe objective of the present study was to investigate whether the Wnt/?-catenin signaling pathway was involved in regulating the cellular and molecular mechanisms of fibrosis in endometriosis in vitro and to evaluate whether fibrosis could be prevented by targeting the Wnt/?-catenin pathway in a xenograft model of endometriosis in immunodeficient nude mice.MethodsSeventy patients (40 with and 30 without endometriosis) with normal menstrual cycles were recruited. In vitro effects of small-molecule antagonists of the Tcf/?-catenin complex (PKF 115-584 and CGP049090) on fibrotic markers (alpha smooth muscle actin, type I collagen, connective tissue growth factor, fibronectin) and collagen gel contraction were evaluated in endometrial and endometriotic stromal cells from patients with endometriosis. In vitro effects of activation of the Wnt/?-catenin signaling pathway by treatment with recombinant Wnt3a on profibrotic responses were evaluated in endometrial stromal cells of patients without endometriosis. The effects of CGP049090 treatment on the fibrosis of endometriotic implants were evaluated in a xenograft model of endometriosis in immunodeficient nude mice.ResultsTreatment with PKF 115-584 and CGP049090 significantly decreased the expression of alpha smooth muscle actin, type I collagen, connective tissue growth factor and fibronectin mRNAs in both endometriotic and endometrial stromal cells with or without transforming growth factor-?1 stimulation. Both endometriotic and endometrial stromal cell-mediated contraction of collagen gels was significantly decreased by treatment with PKF 115-584 and CGP049090 as compared to that of untreated cells. The animal experiments showed that CGP049090 prevented the progression of fibrosis and reversed established fibrosis in endometriosis.ConclusionAberrant activation of the Wnt/?-catenin pathway may be involved in mediating fibrogenesis in endometriosis.

Project description:Background: Homeobox cut like 1 (CUX1), which often presents aberrated expression in many cancer cells, exerts a crucial role in tumorigenesis. Evidence describing CUX1 in gliomagenesis is scarce, and the effects of CUX1 on the Wnt/β-catenin pathway have not been reported. Our study aimed to explore the biological functions and molecular mechanisms involved in CUX1 activity in glioma. Methods: Datasets for bioinformatics analysis were obtained from the GEO, TCGA, CGGA, GTEX and CCLE databases. qRT-PCR, western blotting (WB), and immunohistochemistry (IHC) assays were used to investigate the expression patterns of CUX1 among glioma and brain tissues. CUX1 knockdown and overexpression vectors were transfected into glioma cell lines, the CCK-8, clone formation assay, wound healing, Transwell assay, and flow cytometry were performed to detect changes in cell viability, invasiveness, and the cell cycle. WB and immunofluorescence (IF) assays were used to explore changes in cell cycle-related and Wnt/β-catenin signaling protein levels. Results: Overexpression of CUX1 was identified in glioma tissues, and especially in glioblastoma (GBM), when compared to normal controls and correlated with poor prognosis. In comparison with untreated cells, TJ905 glioma cells overexpressing CUX1 showed higher proliferation and invasion abilities and S phase cell-cycle arrest, while the knockdown of CUX1 suppressed cell invasive ability and induced G1 phase arrest. Active Wnt/β-catenin signaling was enriched and clustered in a CUX1-associated GSEA/GSVA analysis. IF and WB assays indicated that CUX1 regulated the distribution of Axin2/β-catenin in glioma cells and regulated the expression of proteins downstream of the Wnt/β-catenin signaling pathway, suggesting that CUX1 served as an upstream positive regulator of the Wnt/β-catenin pathway. Finally, the knockdown of Axin2 or β-catenin could reverse the tumor-promoting effects caused by CUX1 overexpression, suggesting that CUX1 induced gliomagenesis and malignant phenotype by activating the Wnt/β-catenin signaling pathway. Conclusion: Our data suggested that the transcription factor CUX1 could be a novel therapeutic target for glioma with gene therapy.

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FOXP1 enhances fibrosis via activating Wnt/?-catenin signaling pathway in endometriosis.

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FOXP1 enhances fibrosis via activating Wnt/β-catenin signaling pathway in endometriosis.

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