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Guanylate binding protein 5 accelerates gastric cancer progression via a JAK1-STAT1/GBP5/CXCL8 positive feedback loop

ABSTRACT: Guanylate binding protein 5 accelerates gastric cancer progression via a JAK1-STAT1/GBP5/CXCL8 positive feedback loop

PROVIDER: PRJNA897911 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22179063_1.fastq.gz	Fastqsanger.gz
	SRR22179063_2.fastq.gz	Fastqsanger.gz
	SRR22179064_1.fastq.gz	Fastqsanger.gz
	SRR22179064_2.fastq.gz	Fastqsanger.gz
	SRR22179065_1.fastq.gz	Fastqsanger.gz

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Guanylate binding protein 5 accelerates gastric cancer progression via a JAK1-STAT1/GBP5/CXCL8 positive feedback loop

Project description:To verify the role of GBP5 in GC progression, we established GBP5 -overexpressed MKN45 cells and control cells. We then performed gene expression profiling analysis using data obtained from RNA-seq of 2 different cells with 3 duplicates each.

2024-10-29 | GSE217209 | GEO

Guanylate binding protein 5 accelerates gastric cancer progression via the <i>JAK1-STAT1/GBP5/CXCL8</i> positive feedback loop.

Project description:Guanylate binding protein 5 (GBP5) is a member of the interferon (IFN)-inducible large guanosine triphosphate hydrolases (GTPase) family that regulates cell-autonomous immunity and malignant tumor transformation. However, its specific roles and underlying mechanisms GBP5 in gastric cancer (GC) remain unknown. In this study, we aimed to determine the role GBP5 and underlying mechanism of GBP5 in GC cell progression. Potential oncogenic roles of GBP5 in GC as well as its relationship with the tumor immune microenvironment (TIME) were comprehensively evaluated using bioinformatics analysis. Protein expression levels of GBP5 and their correlation with clinicopathological features of patients were assessed using immunohistochemistry. In addition, diverse in vitro functional experiments were performed to identify the functions of GBP5 in GC. Downstream targets of GBP5 were identified using RNA-sequencing analysis and verified using western blotting or quantitative polymerase chain reaction analysis in different cell lines. GBP5 expression is commonly upregulated and promotes the proliferation and migration of GC cells. Mechanistically, GBP5 was regulated by the IFNγ-Janus kinase (JAK1)-signal transducer and activator of transcription 1 (STAT1) axis and induced CXCL8 expression. Interestingly, GBP5-induced CXCL8 regulated the JAK1-STAT1 signaling pathway to form a positive feedback loop. Moreover, GBP5 is closely related to the TIME and may be used as a biomarker for predicting the efficacy of immunotherapy. Our findings revealed a new JAK1-STAT1/GBP5/CXCL8 pathway and highlighted the value of GBP5 as a predictive biomarker and novel target for GC intervention.

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The LIM protein AJUBA promotes colorectal cancer cell survival through suppression of JAK1/STAT1/IFIT2 network

Project description:Background and Aims: The LIM protein AJUBA participates in the regulation of cell adhesion, mitosis, DNA damage, cell differentiation, proliferation, migration and gene transcription, yet its roles in tumor development and progression are poorly defined. The aim is to determine the role of AJUBA in colorectal tumorigenesis. Methods: We performed data mining in Oncomine databases and immunohistochemistry (IHC) assays on 67 paired colorectal cancer (CRC) samples; we manipulated the AJUBA expression in SW-1116 and Caco-2 cells using specific shRNA and overexpression plasmids and performed assays for cell viability, cell cycle and apoptosis; we performed RNA-seq and qRT-PCR assays to identify genes regulated by AJUBA; we performed western blot, co-immunoprecipitation assays to study the interaction of AJUBA and JAK/STAT; Results: We discovered that AJUBA is highly expressed in CRC and promotes CRC cell growth in culture and in xenograted mice via an inhibition of apoptosis by repression of the IFIT2 gene. AJUBA specifically binds the FERM domain of JAK1 to dissociate JAK1 from the IFNγ recepter, resulted in inhibition of STAT1 phosporylation and concomitantly its nuclear translocation. Clinically, the level of AJUBA in CRC specimens is negatively correlated with the levels of IFIT2 and pSTAT1. Conclusion: Ajuba functions as a specific suppressor of the Interferon-activated JAK1/STAT1 signaling to promote colorectal cancer development via an inhibition of Interferon induced apoptosis.

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Revealing an unconventional JAK1/2-STAT3 branch in macrophage IFNγ signaling [ChIP-Seq]

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Profiling of transcriptional targets of Jak1 and Stat1 in proliferating and differentiating myoblasts

Project description:Styxl2, a poorly characterized pseudophosphatase, was identified as a transcriptional target of the Jak1-Stat1 pathway during myoblast differentiation in culture. Styxl2 is specifically expressed in vertebrate striated muscles. By gene knockdown in zebrafish or genetic knockout in mice, we found that Styxl2 plays an essential role in maintaining sarcomere integrity in developing muscles. To further reveal the functions of Styxl2 in adult muscles, we generated two inducible knockout mouse models: one with Styxl2 being deleted in mature myofibers to assess its role in sarcomere maintenance, and the other in adult muscle satellite cells (MuSCs) to assess its role in de novo sarcomere assembly. We find that Styxl2 is not required for sarcomere maintenance but functions in de novo sarcomere assembly during injury-induced muscle regeneration. Mechanistically, Styxl2 interacts with non-muscle myosin IIs, enhances their ubiquitination, and targets them for autophagy-dependent degradation. Without Styxl2, the degradation of non-muscle myosin IIs is delayed, which leads to defective sarcomere assembly and force generation. Thus, Styxl2 promotes de novo sarcomere assembly by interacting with non-muscle myosin IIs and facilitating their autophagic degradation.

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Type I and II interferons drive inflammation through STAT1 in murine macrophage activation syndrome.

Project description:Macrophage activation syndrome (MAS) exemplifies a cytokine storm syndrome by liver inflammation whereby interferon (IFN)-γ, which activates the JAK1/2-STAT1 pathway, is being a key driver cytokine. Ruxolitinib, a JAK1/2 inhibitor, has shown promising results in treating MAS patients, however the exact mechanism responsible for disease remission is unclear. One of the mediators inhibited by Ruxolitinib is STAT1, but its role in MAS pathogenesis remains unexplored. In this study, we explored the hepatic immune landscape of MAS and the role of STAT1 herein, using a Toll-like receptor (TLR)9-induced murine model of MAS. Cellular indexing of transcriptomes and epitopes-single cell RNA sequencing (CITE-seq) was performed on the immune compartment of the livers from wild-type (WT) and STAT1 knockout (KO) mice in naive conditions and upon induction of MAS.

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