Down-regulation of FABP5 suppresses the proliferation and induces apoptosis in gastric cancer cells through Hippo signaling pathway
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE171838 | GEO | 2022/12/31
REPOSITORIES: GEO
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Project description:Background: Gastric cancer (GC) is the second most lethal cancer globally and is associated with poor prognosis. Fatty acid-binding proteins (FABPs) can regulate the biological properties of carcinoma cells. FABP5 is overexpressed in many types of cancers; however, the role and mechanism of FABP5 in GC are still unclear. Aim: In this study, we aimed to evaluate the clinical and biological function of FABP5 in GC. Methods: We assessed FABP5 expression using immunohistochemical analysis of 79 GC patients and evaluated its biological functions following in vitro and in vivo ectopic expression. FABP5 targets relevant to GC progression were determined using RNA sequencing (RNA-seq) analyses. Results: Elevated FABP5 expression was closely related to poor outcomes, and ectopic expression of FABP5 promoted GC cell proliferation, invasion, migration, and carcinogenicity, suggesting its potential tumor-promoting role in GC. Additionally, RNA-seq analysis indicated that FABP5 activates immune-related pathways, including cytokine–cytokine receptor-interaction pathways, interleukin-17 signaling, and tumor necrosis factor signaling, suggesting an important rationale for the possible development of therapies combining FABP5-targeted drugs with immunotherapeutics. Conclusion: These findings highlight the biological mechanisms and clinical implications of FABP5 in GC and suggest its potential as an adverse prognostic factor and/or therapeutic target.
2023-12-31 | GSE218422 | GEO
Project description:The Hippo pathway is an emerging signaling cascade involved in the regulation of organ size control. It consists of evolutionally conserved protein kinases that are sequentially phosphorylated and activated. The active Hippo pathway subsequently phosphorylates a transcription coactivator, YAP, which precludes its nuclear localization and transcriptional activation. Identification of transcriptional targets of YAP in diverse cellular contexts is therefore critical to the understanding of the molecular mechanisms in which the Hippo pathway restricts tissue growth. We used microarrays to profile the gene expression patterns upon acute siRNA knockdown of Hippo pathway components in multiple mammalian cell lines and identified a set of genes representing immediate transcriptional targets of the Hippo/Yap signaling pathway. Three mammalian cell lines (HEK293T, HepG2, HaCaT) were transfected with scramble siRNA controls or siRNAs against NF2 and LATS2, two core components of the Hippo pathway, simultaneously. Total RNAs were harvested four days after transfection to reveal the gene expression pattern unsing microarry. YAP and TAZ siRNAs were also transfected along with NF2 and LATS2 siRNAs to identify YAP/TAZ-dependent transcriptional targets upon loss of NF2/LATS2.
2013-12-31 | E-GEOD-49384 | biostudies-arrayexpress
Project description:Purpose: Mouse BMDM is the universal cell type of studying innate immunity. This study was designed to analyze LPS induced innate immune response and the gene expression in FABP5 KO BMDMs with overexpression of FABP5 WT or FABP5 C127S. Methods: FABP5 KO BMDMs were nucleofected with 5 μg pXJ40-3xFlag-FABP5 WT or C127S plasmid using the Amaxa Mouse Macrophage Nucleofector Kit (Lonza, VPA-1009) following the manufacturer’s instructions. Replace medium 6 hours post Nucleofection and add 500 ng/mL LPS to the fresh medium. 24 hours after treatment, harvest cells by using GenElute Single Cell RNA Purification Kit (Sigma, RNB300) and perform RNA-seq. Then mRNA profiles of these samples were generated by high-throughput sequencing analysis, using Illumina NovaSeq6000. And the differential mRNA profiles were analyzed. Results: mRNA profiles were analyzed, and differential expression profiles were compared. Conclusions: Our study demonstrated the transcriptional profiles of FABP5 KO BMDMs with overexpression of FABP5 WT or FABP5 C127S upon LPS treatment, with biologic replicates, generated by RNA-seq technology.
2021-11-01 | GSE182238 | GEO
Project description:The Hippo pathway is a commonly altered signaling pathway involved in cancer initiation and progression; however, exactly how this pathway becomes dysregulated to promote human cancer development has not been fully understood. In this study, we systematically analyzed the Hippo somatic mutations derived from human cancer genome and functionally annotated their roles in targeting the Hippo pathway. We identified a total of 85 driver missense mutations for the major Hippo pathway genes and elucidated the mechanisms by which these mutations altered their functions in the Hippo pathway. Through these analyses, we revealed zinc-finger domain (ZNF) as an integral structure required for MOB1 function, whose driver mutations promoted head and neck cancer development. Moreover, we discovered that the schwannoma/meningioma-derived NF2 driver mutations gained an oncogenic role by activating the VANGL-JNK pathway. Taken together, our study offers a rich somatic mutation resource for further investigating the Hippo pathway in human cancer, providing a molecular basis for the development of Hippo-related personalized cancer therapy.
2024-10-18 | PXD049472 | Pride
Project description:The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Its dysregulation has been well-studied to promote tumor initiation and progression, including gastric cancer (GC). Although the Hippo-YAP1 signaling pathway regulates the expression of thousands of target genes, how these target genes contribute to the oncogenic program driven by YAP1 remains unknown. Here we identified the vital role of FOXP4 in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Knocking down FOXP4 impairs GC spheroid formation and inhibits stemness marker expression, while its upregulation potentiates the cancer cells with more stemness. RNA-seq analysis revealed SOX12 as functional downstream of FOXP4 in the YAP1-induced carcinogenesis. Targeting FOXP4 by 42-(2-Tetrazolyl) rapamycin in GC cells enhanced the 5-FU efficacies. Our findings have unveiled FOXP4 as a novel stemness marker that promotes tumorigenesis by upregulating SOX12. Additionally, we have identified FOXP4 as a direct target for modulating YAP1 signaling in GC. Therefore, the YAP1-FOXP4-SOX12 axis presents a promising therapeutic target for GC.
2024-07-13 | GSE267854 | GEO
Project description:Skin inflammation and photosensitivity are common manifestations of cutaneous and systemic lupus erythematosus (SLE), yet the underlying mechanisms are poorly understood. Non-lesional SLE skin exhibits increased UVB-driven cell death that persists in culture, supporting a potential role for epigenetic modifications to sustain this phenotype. We thus examined differential DNA methylation of non-lesional SLE vs. healthy control keratinocytes (KC) and identified Hippo signaling as the top significantly differentially methylated pathway, likely driven by hypomethylation of WWC1, a scaffold protein and Hippo pathway regulator. Analysis of non-lesional SLE skin biopsies and SLE keratinocytes in culture confirmed WWC1 overexpression that led to enhanced phosphorylation of YAP resulting in a pro-apoptotic transcriptional profile reflective of decreased YAP/TEAD transcriptional coactivation. Functional studies of UV-mediated apoptosis confirmed a regulatory role for YAP/TEAD interactions, and blockade of overactive Hippo signaling via a LATS1/2 inhibitor abrogated enhanced apoptosis in SLE KCs. Thus, our work identifies a novel mechanistic paradigm in SLE KCs in which aberrant UVB-apoptosis is driven by Hippo signaling via promotion of YAP phosphorylation and restriction of YAP coactivation of TEAD transcriptional activity. Hippo modulation may be a novel target for photosensitivity in SLE and CLE.
2023-07-06 | GSE198972 | GEO
Project description:The Hippo signaling pathway has become recognized as a context-dependent regulator of cell proliferation, differentiation, and apoptosis in species ranging from Drosophila to human. In this study, we sought to understand whether Hippo signaling plays a role in pancreatic development and organ homeostasis. We analyzed mRNA from 5 samples each from control and DKO mouse pancreas using Affymetrix MouseGene 1.0 ST Array platfrom. Array data was processed by Affymetrix array computational tools.
2013-02-14 | E-GEOD-44298 | biostudies-arrayexpress
Project description:The Hippo pathway is an emerging signaling cascade involved in the regulation of organ size control. It consists of evolutionally conserved protein kinases that are sequentially phosphorylated and activated. The active Hippo pathway subsequently phosphorylates a transcription coactivator, YAP, which precludes its nuclear localization and transcriptional activation. Identification of transcriptional targets of YAP in diverse cellular contexts is therefore critical to the understanding of the molecular mechanisms in which the Hippo pathway restricts tissue growth. We used microarrays to profile the gene expression patterns upon acute siRNA knockdown of Hippo pathway components in multiple mammalian cell lines and identified a set of genes representing immediate transcriptional targets of the Hippo/Yap signaling pathway.
2013-12-31 | GSE49384 | GEO
Project description:As a classic tumor suppressor pathway, Hippo signaling axis is activated by various extra-pathway factors to regulate cell differentiation and organ development. However, recent studies have reported that the activation of Hippo signaling pathway may be more dependent on the autophosphorylation of its core kinase cassette. Here, we demonstrate that protein arginine methyltransferase 5 (PRMT5) is involved in inducing the inactivation of Hippo signaling pathway in pancreatic cancer. Our study shows that the initiator serine/threonine kinase 3 (STK3, also known as MST2) of Hippo signaling pathway can be symmetrically di-methylated at arginine-461 (R461) and arginine-467 (R467) in the SARAH domain by PRMT5, and the methylated MST2 suppresses its autophosphorylation and kinase activity by blocking the formation of homodimer, thereby inactivating Hippo signaling pathway in pancreatic cancer. Moreover, we also discover that the specific PRMT5 inhibitor GSK3326595 re-activates the dysregulated Hippo signaling pathway and inhibits the growth of human-derived pancreatic cancer xenografts in immunodeficient mice, which provides a theoretical foundation for the clinical application of PRMT5 inhibitor in pancreatic cancer.
2023-11-17 | GSE241402 | GEO
Project description:Mutations that lead to hyperactivation of Ras signaling are hallmarks of carcinomas. During development, signaling via Ras mediates cell fate decisions and cellular differentiation without causing hyper-proliferation. What determines whether Ras activation leads to differentiation or proliferation remains unknown. Here we show that the Hippo pathway reprograms the cellular response to Ras signaling in Drosophila. While hyperactivation of Ras signaling alone promotes cellular differentiation, additional loss of Hippo signaling drives aggressive hyper-proliferation. Transcriptome analysis combined with ChIP-nexus confirmed that the magnitude and specificity of Ras target gene expression strongly depends on the activity status of the Hippo pathway. This is because Hippo signaling directly regulates the expression of two key downstream transcription factors of the Ras pathway: the ETS-domain transcription factor Pointed and the transcriptional repressor Capicua. Our results highlight how independent signaling pathways can impinge on each other at the level of transcription factors, thereby providing a safety mechanism to keep proliferation in check under normal developmental conditions.
2017-09-26 | GSE96868 | GEO