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Yes-Associated Protein (YAP) Induces a Secretome Phenotype and Transcriptionally Regulates Plasminogen Activator Inhibitor-1 (PAI-1) Expression in Hepatocarcinogenesis

ABSTRACT: To investigate how tumour cell-derived YAP is changing the paracrine communication network between tumour cells and non-tumorous cells in hepatocarcinogenesis, the expression and secretion of cytokines, growth factors and chemokines were analysed in transgenic mice with liver-specific and inducible expression of constitutively active human YAP (YAPS127A). Transcriptome analysis of primary isolated hepatocytes revealed that YAP overexpression induced the expression and secretion of many paracrine-acting factors with potential impact on other tumorous or non-tumorous cells (e.g. plasminogen activator inhibitor-1 (PAI-1), C-X-C motif chemokine ligand 13 (CXCL13), CXCL16).

ORGANISM(S): Mus musculus

PROVIDER: GSE128043 | GEO | 2020/09/15

REPOSITORIES: GEO

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Expression profiling of Sk-Hep1 after PAI-1 silencing (RNAi)

Project description:Methods: To investigate how tumor cell-derived YAP is changing the paracrine communication network between tumor cells and non-tumorous cells in hepatocarcinogenesis, the expression and secretion of cytokines, growth factors and chemokines were analyzed in transgenic mice with liver-specific and inducible expression of constitutively active YAP (YAPS127A). Transcriptomic and proteomic analyses were performed using primary isolated hepatocytes and blood plasma. In vitro, RNAinterference (RNAi), expression profiling, functional analyses and chromatin immunoprecipitation (ChIP) analyses of YAP and the transcription factor TEA domain transcription factor 4 (TEAD4) were performed using immortalized cell lines. Findings were confirmed in cohorts of HCC patients at the transcript and protein levels. Results: YAP overexpression induced the expression and secretion of many paracrine-acting factors with potential impact on other tumorous or non-tumorous cells (e.g. plasminogen activator inhibitor-1 (PAI-1), C-X-C motif chemokine ligand 13 (CXCL13), CXCL16). Expression analyses of human HCC patients showed an overexpression of PAI-1 in human HCC tissues and a correlation with poor overall survival as well as early cancer recurrence. PAI-1 statistically correlated with genes typically induced by YAP, such as connective tissue growth factor (CTGF) and cysteine rich angiogenic inducer 61 (CYR61) or YAP-dependent gene signatures (CIN4/25). In vitro, YAP inhibition diminished the expression and secretion of PAI-1 in murine and human liver cancer cell lines. PAI-1 affects the expression of genes involved in proliferation as well as cellular senescence and oncogene-induced senescence was confirmed in YAPS127A transgenic mice. Silencing of TEAD4 as well as treatment with the YAP/TEAD interfering substance Verteporfin reduced PAI-1 expression. ChIP analyses confirmed the binding of YAP and TEAD4 to the gene promoter of PAI-1 (SERPINE1).

2020-10-28 | GSE150796 | GEO

RNA-seq of tumor cells sorted from YAPS127A and BrafV600E/YAPS127A mouse thyroid tumors

Project description:We performed high-throughput RNA sequencing of tumor cells sorted from YAPS127A and BrafV600E/YAPS127A to investigate YAP dependency and driver cooperativity in thyroid tumor progression.

2023-03-09 | GSE198381 | GEO

RNA-seq of human thyroid cancer cell lines expressing sh-mirE-YAP or YAPS127A

Project description:We performed high-throughput RNA sequencing of stable lines with dox-inducible expression of sh-mirE-YAP or of the constitutively nuclear YAPS127A mutant to investigate YAP dependency and its role in tumorogenesis.

2023-03-09 | GSE198379 | GEO

Yes-associated protein (YAP) induces a secretome phenotype and transcriptionally regulates plasminogen activator Inhibitor-1 (PAI-1) expression in hepatocarcinogenesis.

Project description: Not available

| S-EPMC7583285 | biostudies-literature

Identification of YAP-TEAD gene signatures in metastatic melanoma

Project description:YAP1 (Yes-associated protein 1) is transcriptional co-activator that partners with the TEAD family of transcription factors to regulate gene expression. Increased YAP-TEAD activity is strongly implicated in the development, progression, and metastasis of several cancer types including melanoma, but the YAP-TEAD target genes that are responsible for YAP-TEAD-dependent melanoma progression and metastasis are largely unknown. To identify YAP-TEAD regulated genes in metastatic melanoma cells we used RNA-sequencing to compare gene expression in control A375 human melanoma cells to A375 cells expressing mutant forms of YAP with increased transcriptional activity due to the mutation of LATS inhibitory phosphorylation sites (YAPS127A or YAPS127A,S381A). To determine which YAP-dependent gene expression changes are mediated by TEADs we also included a mutant form of YAP that is unable to bind TEADS (YAPS94A,S127A).

2024-03-29 | GSE234083 | GEO

PAI-1, the Plasminogen System, and Skeletal Muscle.

Project description: Not available

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Oocyte-expressed Yes-associated Protein (YAP) is a Key Activator of the Early Zygotic Genome in Mouse

Project description:We generated maternal and paternal mouse models with Yap1-deletion, and elucidated the function of maternal YAP in zygotic genome activation. RNA sequencing with 2 WT oocyte samples at GV stage, 2 YAP-/- oocyte samples at GV stage, 1 WT embryo samples at 4cell stage, 1 YAP-/- embryo samples at at 4-cell stage.

2016-02-28 | E-GEOD-74344 | biostudies-arrayexpress

Plasminogen activator inhibitor-1 (PAI-1) expression in endometriosis.

Project description: Not available

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Yes-Associated Protein (YAP) Induces a Secretome Phenotype and Transcriptionally Regulates Plasminogen Activator Inhibitor-1 (PAI-1) Expression in Hepatocarcinogenesis

Project description:Yes-Associated Protein (YAP) Induces a Secretome Phenotype and Transcriptionally Regulates Plasminogen Activator Inhibitor-1 (PAI-1) Expression in Hepatocarcinogenesis

| PRJNA526204 | ENA

YAP/TAZ-dependent expression of lncRNAs [A549]

Project description:Body fluids from cancer patients are informative regarding disease conditions in tumor tissues. Thus, biomarkers detected by liquid biopsy can guide clinicians in designing personalized therapies and may serve as a proxy for treatment success. However, biomarkers that predict the existence of druggable target structures cannot be reliably defined in blood samples due to genetic tumor heterogeneity and presence of molecules from non-tumorous cells. To test the applicability of RNA signatures as liquid biopsy biomarkers, expression data from hepatocellular carcinoma (HCC) cells after inhibition of Hippo pathway effectors is investigated. We show that the oncogene yes-associated protein (YAP) transcriptionally controls a panel of long non-coding RNAs (lncRNAs), which support HCC progression via tumor cell-intrinsic mechanisms. These lncRNAs are detectable and overexpressed in YAPS127A transgenic mouse livers as well as in a subgroup of human HCC tissue and serum samples. Using a machine learning algorithm, a 4 gene lncRNA signature is defined that correlates with the nuclear abundance of YAP in HCC tissues (CYTOR, SNHG1, SNHG17, MIR4435-2HG). Importantly, YAP accumulation in human HCCs is significantly associated with lncRNA signature serum abundance in two independent patient cohorts. Evaluation of expression data and confirmatory experiments illustrate that the lncRNA signature is a robust predictor for YAP activity in other tumor types such as lung adenocarcinoma. Liquid biopsy-based detection of lncRNAs in cancer patients is informative for the activity of transcriptional regulators and can serve as diagnostic tool that guides clinicians in the design of targeted therapies.

2023-03-15 | GSE207723 | GEO

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