Guanylate Binding Protein 2 Research Articles

GBP2 Regulates Lipid Metabolism by Inhibiting the HIF-1 Pathway to Alleviate the Progression of Allergic Rhinitis.

Allergic rhinitis (AR) is a prevalent allergic disorder instigated by a variety of allergenic stimuli. The study aims to elucidate the mechanistic underpinnings of Guanylate-binding protein 2 (GBP2) in modulating AR. Bioinformatics analysis was used to identify hub genes in AR, and GBP2 was identified. Mice were injected with ovalbumin (OVA) to create AR model. The pathological changes of the nasal mucosa were observed by hematoxylin-eosin staining. ELISA and western blot demonstrated that in OVA-induced AR mice, high IgE and IgG1 levels, inflammation (increased TNF-α, IL-5 and IFN-γ), oxidative stress (high ROS, low TAOC and GSH) and abnormal lipid metabolism (increased TC and LDL-C, decreased HLD-C) were observed. Mouse nasal mucosal epithelial cells (MNECs) were treated with TNF-α to simulate AR. Cell viability and apoptosis were evaluated by CCK-8 assay and flow cytometer, respectively. In vitro assay revealed that GBP2 inhibited total IgE, OVA-IgE and IgG1 levels and suppressed abnormal lipid metabolism, inflammation and oxidative stress to alleviate AR. Furthermore, HIF-1 pathway was screened as the downstream pathway of GBP2. GBP2 inhibited the HIF-1 pathway, and Fenbendazole-d3, the activator of HIF-1 pathway, weakened the inhibitory effects of GBP2 on apoptosis, inflammation, oxidative stress and abnormal lipid metabolism in vitro. In summary, GBP2 alleviated abnormal lipid metabolism, inflammation and oxidative stress by inhibiting the HIF-1 pathway, providing a direction for the treatment of AR.

CENPA facilitates glioma stem cell stemness and suppress ferroptosis to accelerate glioblastoma multiforme progression by promoting GBP2 transcription

The function of glioma stem cells (GSCs) is closely related to the progression of glioblastoma multiforme (GBM). Centromere protein A (CENPA) has been confirmed to be related to the poor prognosis of GBM patients. However, whether CENPA regulates GSCs function to mediate GBM progression is still unclear. GSCs were isolated from GBM cells. The expression of CENPA and guanylate-binding protein 2 (GBP2) was examined by quantitative real-time PCR and western blot. GSCs proliferation and stemness were assessed using EdU assay and sphere formation assay. Cell ferroptosis was evaluated by detecting related factors. The interaction between CENPA and GBP2 was analyzed by ChIP assay and dual-luciferase reporter assay. Animal experiments were conducted to measure the effect of CENPA knockdown on the tumorigenicity of GSCs in vivo. CENPA was upregulated in GBM tissues and GSCs. CENPA knockdown inhibited GSCs proliferation, stemnness, and promoted ferroptosis. GBP2 was overexpressed in GBM tissues and GSCs, and CENPA enhanced GBP2 transcription by binding to its promoter region. CENPA overexpression accelerated GSCs proliferation and stemnness and suppressed ferroptosis, while GBP2 knockdown reversed these effects. Downregulation of CENPA reduced the tumorigenicity of GSCs by decreasing GBP2 expression in vivo. In conclusion, CENPA enhanced GBP2 transcription to increase its expression, thus accelerating GSCs proliferation and stemnness and repressing ferroptosis. Our findings promote a new idea for GBM treatment.

Identification of Immune-Related Gene Signature in Schizophrenia.

Schizophrenia (SCZ) is a type of psychiatric disorder characterized by multiple symptoms. Our aim is to decipher the relevant mechanisms of immune-related gene signatures in SCZ. The SCZ dataset and its associated immunoregulatory genes were retrieved using Gene Expression Omnibus (GEO) and single-sample gene set enrichment analysis (ssGSEA). Co-expressed gene modules were determined through weighted gene correlation network analysis (WGCNA). To elucidate the functional characteristics of these clusters, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used. Additionally, gene set enrichment analysis (GSEA) and Gene Set Variation Analysis (GSVA) were conducted to identify enriched pathways for the immune subgroups. A protein-protein interaction (PPI) network analysis was performed to identify core genes relevant to SCZ. A significantly higher immune score was observed in SCZ compared to control samples. Seven distinct gene modules were identified, with genes highlighted in green selected for further analysis. Using the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) method, degrees of immune cell adhesion and accumulation related to 22 different immune cell types were calculated. Significantly enriched bioprocesses concerning the immunoregulatory genes with differential expressions included interferon-beta, IgG binding, and response to interferon-gamma, according to GO and KEGG analyses. Eleven hub genes related to immune infiltration emerged as key players among the three top-ranked GO terms. This study underscores the involvement of immunoregulatory reactions in SCZ development. Eleven immune-related genes (IFITM1 (interferon induced transmembrane protein 1), GBP1 (guanylate binding protein 1), BST2 (bone marrow stromal cell antigen 2), IFITM3 (interferon induced transmembrane protein 3), GBP2 (guanylate binding protein 2), CD44 (CD44 molecule), FCER1G (Fc epsilon receptor Ig), HLA-DRA (major histocompatibility complex, class II, DR alpha), FCGR2A (Fc gamma receptor IIa), IFI16 (interferon gamma inducible protein 16), and FCGR3B (Fc gamma receptor IIIb)) were identified as hub genes, representing potential biomarkers and therapeutic targets associated with the immune response in SCZ patients.

Exploring the Role of Guanylate-Binding Protein-2 in Activated Microglia-Mediated Neuroinflammation and Neuronal Damage.

Neuron damage by microglia, which act as macrophage cells in the brain, can result in various brain diseases. However, the function of pro-inflammatory or anti-inflammatory microglia in the neurons remains controversial. Guanylate-binding protein-2 (GBP2) is expressed and activated in the microglia in the early phase of the inflammatory response and plays an important role in controlling immune responses. In this study, we evaluated whether GBP2 initially reduces the immune response induced by microglia, and whether microglia induce pro-inflammatory functions in neurons via GBP2 expression. In lipopolysaccharide (LPS)-stimulated microglia, we assessed the expression of GBP2 and how it affects neurons via activated microglia. The biological functions of microglia due to the downregulation of the GBP2 gene were examined using short hairpin RNA (shRNA)-RNA-GBP2. Downregulated GBP2 affected the function of mitochondria in the microglia and showed reduced neuronal damage when compared to the control group in the co-culture system. Furthermore, this protein was observed to be highly expressed in the brains of dementia mice. Our results are the first to report that the downregulation of GBP2 in activated microglia has an anti-inflammatory function. This study suggests that the GBP2 gene can be used as a therapeutic target biomarker for inflammation-related neurodegenerative diseases.

GBP2 inhibits pathological angiogenesis in the retina via the AKT/mTOR/VEGFA axis

Pathological retinal angiogenesis is not only the hallmark of retinopathies, but also a major cause of blindness. Guanylate binding protein 2 (GBP2) has been reported to be associated with retinal diseases such as diabetic retinopathy and hypoxic retinopathy. However, GBP2-mediated pathological retinal angiogenesis remains largely unknown. The present study aimed to investigate the role of GBP2 in pathological retinal angiogenesis and its underlying molecular mechanism. In this study, we established oxygen-induced retinopathy (OIR) mice model for in vivo study and hypoxia-induced angiogenesis in ARPE-19 cells for in vitro study. We demonstrated that GBP2 expression was markedly downregulated in the retina of mice with OIR and ARPE-19 cells treated with hypoxia, which was associated with pathological retinal angiogenesis. The regulatory mechanism of GBP2 in ARPE-19 cells was studied by GBP2 silencing and overexpression. The regulatory mechanism of GBP2 in the retina was investigated by overexpressing GBP2 in the retina of OIR mice. Mechanistically, GBP2 downregulated the expression and secretion of vascular endothelial growth factor (VEGFA) in ARPE-19 cells and retina of OIR mice. Interestingly, overexpression of GBP2 significantly inhibited neovascularization in OIR mice, conditioned medium of GBP2 overexpressing ARPE-19 cells inhibited angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, we confirmed that GBP2 downregulated VEGFA expression and angiogenesis by inhibiting the AKT/mTOR signaling pathway. Taken together, we concluded that GBP2 inhibited pathological retinal angiogenesis via the AKT/mTOR/VEGFA axis, thereby suggesting that GBP2 may be a therapeutic target for pathological retinal angiogenesis.

GBP2 upregulated in LPS-stimulated macrophages-derived exosomes accelerates septic lung injury by activating epithelial cell NLRP3 signaling

Macrophages infiltration is a crucial factor causing Sepsis-associated acute lung injury (ALI). Accumulating evidence suggests macrophages-alveolar epithelial cells communication is proven to be critical in ALI. However, little is known regarding how activated macrophages regulated sepsis-associated ALI. To explore the role of macrophages-alveolar epithelial cells communication in the ALI process, our data revealed that Lipopolysaccharides-induced macrophages-derived exosomes (L-Exo) induced sepsis-associated ALI and caused alveolar epithelial cells damage. Moreover, Guanylate-binding protein 2 (GBP2) was significantly upregulated in L-Exo, and NLRP3 inflammasomes was the direct target of GBP2. Further experimentation showed that GBP2 inhibition in vitro and in vivo reserves L-Exo effects, while GBP2 overexpression in vitro and in vivo promotes L-Exo effects. These results demonstrated that L-Exo contains excessive GBP2 and promotes inflammation through targeting NLRP3 inflammasomes, which induced alveolar epithelial cells dysfunction and pyroptosis. These findings demonstrate that L-Exo exerted a deleterious effect on ALI by regulating the GBP2/NLRP3 axis, which might provide new insight on ALI prevention and treatment.

GBP2 is a prognostic biomarker and associated with immunotherapeutic responses in gastric cancer

BackgroundThe interferon-induced protein known as guanylate-binding protein 2 (GBP2) has been linked to multiple different cancer types as an oncogenic gene. Although the role of GBP2 in cancer has been preliminarily explored, it is unclear how this protein interacts with tumor immunity in gastric cancer.MethodsThe expression, prognostic value, immune-correlations of GBP2 in gastric cancer was explored in multiple public and in-house cohorts. In addition, the pan-cancer analysis was performed to investigate the immunological role of GBP2 based on The Cancer Genome Atlas (TCGA) dataset, and the predictive value of GBP2 for immunotherapy was also examined in multiple public cohorts.ResultsGBP2 was highly expressed in tumor tissues and associated with poor prognosis in gastric cancer. In addition, GBP2 was associated with the immune-hot phenotype. To be more specific, GBP2 was positively related to immuno-modulators, tumor-infiltrating immune cells (TIICs), immunotherapy biomarkers, and even well immunotherapeutic response. In addition to gastric cancer, GBP2 was expected to be an indicator of high immunogenicity in most cancer types. Importantly, GBP2 could predict the immunotherapeutic responses in at least four different cancer types, including melanoma, urothelial carcinoma, non-small cell lung cancer, and breast cancer.ConclusionsTo sum up, GBP2 expression is a promising pan-cancer biomarker for estimating the immunological characteristics of tumors and may be utilized to detect immuno-hot tumors in gastric cancer.

GBP2 promotes clear cell renal cell carcinoma progression through immune infiltration and regulation of PD‑L1 expression via STAT1 signaling.

Guanylate‑binding protein 2 (GBP2) has been widely studied in cancer, however, its potential role in clear cell renal cell carcinoma (ccRCC) is not fully elucidated. The present study aimed to explore the effect of GBP2 on tumor progression and its possible underlying molecular mechanisms in ccRCC. The Cancer Genome Atlas, Gene Expression Omnibus, Cancer Cell Line Encyclopedia databases, and several bioinformatics analysis tools, such as Gene Expression Profiling Interactive Analysis 2, Kaplan‑Meier plotter, UALCAN, LinkedOmics, Metascape, GeneMANIA and Tumor Immune Estimation Resource, were used to characterize the functional relationship between GBP2 and ccRCC. Focusing on the association between GBP2 and programmed death ligand 1 (PD‑L1) invitro, the regulatory mechanism was investigated by knockdown and overexpression of GBP2 in Caki‑1 and 786‑O cells using reverse transcription‑quantitative PCR, western blotting and co‑immunoprecipitation techniques. The results indicated that GBP2 was commonly upregulated in ccRCC, correlating with worse prognosis. In addition, GBP2 expression levels were positively associated with different patterns of immune cell infiltration, suggesting that the GBP2 gene regulates PD‑L1 expression via the signal transducer and activator of transcription 1 (STAT1) pathway. The present study suggested that GBP2 regulates tumor immune infiltration and promotes tumor immune escape through PD‑L1 expression, revealing a potential immunotherapeutic target for ccRCC.

GBP2 acts as a member of the interferon signalling pathway in lupus nephritis

Lupus nephritis (LN) is a common and serious clinical manifestation of systemic lupus erythematosus. However, the pathogenesis of LN is not fully understood. The currently available treatments do not cure the disease and appear to have a variety of side effects in the long term. The purpose of this study was to search for key molecules involved in the LN immune response through bioinformatics techniques to provide a reference for LN-specific targeted therapy. The GSE112943 dataset was downloaded from the Gene Expression Omnibus database, and 20 of the samples were selected for analysis. In total, 2330 differentially expressed genes were screened. These genes were intersected with a list of immune genes obtained from the IMMPORT immune database to obtain 128 differentially expressed immune-related genes. Enrichment analysis showed that most of these genes were enriched in the interferon signalling pathway. Gene set enrichment analysis revealed that the sample was significantly enriched for expression of the interferon signalling pathway. Further analysis of the core gene cluster showed that nine genes, GBP2, VCAM1, ADAR, IFITM1, BST2, MX2, IRF5, OAS1 and TRIM22, were involved in the interferon signalling pathway. According to our analysis, the guanylate binding protein 2 (GBP2), interferon regulatory factor 5 and 2′-5′-oligoadenylate synthetase 1 (OAS1) genes are involved in three interferon signalling pathways. At present, we do not know whether GBP2 is associated with LN. Therefore, this study focused on the relationship between GBP2 and LN pathogenesis. We speculate that GBP2 may play a role in the pathogenesis of LN as a member of the interferon signalling pathway. Further immunohistochemical results showed that the expression of GBP2 was increased in the renal tissues of LN patients compared with the control group, confirming this conjecture. In conclusion, GBP2 is a member of the interferon signalling pathway that may have implications for the pathogenesis of LN and serves as a potential biomarker for LN.

GBP2 as a potential prognostic predictor with immune-related characteristics in glioma.

Guanylate binding protein 2 (GBP2) is a member of the guanine binding protein family, and its relationship with prognostic outcomes and tumor immune microenvironments in glioma remains elusive. We found GBP2 were increased in glioma tissues at both mRNA and protein levels. Kaplan-Meier curves revealed that high GBP2 expression was linked with worse survival of glioma patients, and multivariate Cox regression analysis indicated that high GBP2 expression was an independent prognostic factor for glioma. Combined analysis in immune database revealed that the expression of GBP2 was significantly related to the level of immune infiltration and immunomodulators. Single-cell analysis illustrated the high expression of GBP2 in malignant glioma cells showed the high antigen presentation capability, which were confirmed by real-time polymerase chain reaction (qRT-PCR) data. Additionally, the hsa-mir-26b-5p and hsa-mir-335-5p were predicted as GBP2 regulators and were validated in U87 and U251 cells. Our results first decipher immune-related characteristics and noncoding regulators of GBP2 in glioma, which may provide insights into associated immunotherapies and prognostic predictor.

6-Gingerol attenuates subarachnoid hemorrhage-induced early brain injury via GBP2/PI3K/AKT pathway in the rat model.

Numerous studies have elucidated the neuroprotective effect of 6-gingerol in central nervous system diseases. However, the potential role and mechanism of 6-gingerol on early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains poorly understood. Here, we report that 6-gingerol exerts a neuroprotective effect on SAH-induced EBI through the GBP2/PI3K/AKT pathway. A SAH rat model was established by injecting femoral artery blood into the cisterna magna. 6-gingerol or vehicle was injected intraperitoneally 1 hour post-SAH induction. We found that the neurological function score and brain edema of SAH rats were significantly improved after 6-gingerol treatment, as well as neuronal apoptosis was attenuated in SAH rats by Nissl staining assay and TUNEL assay. To further explore potential molecular mechanisms associated with 6-gingerol, RNA sequencing was implemented to investigate the differences in transcriptomes between SAH rats with and without 6-gingerol treatment; and found that the expression of guanylate-binding protein 2 (GBP2) evidently was suppressed with 6-gingerol treatment compared to vehicle group. In addition, dual immunofluorescence was also employed to investigate changes in neurons, astrocytes, and microglia after 6-gingerol treatment. The results showed that GBP2 was expressed in neurons but not astrocytes or microglia. Western blotting analysis results demonstrated that the PI3K/AKT pathway was activated in the SAH rats treated with 6-gingerol. Furthermore, recombinant GBP2 protein and LY294002 (PI3K inhibitor) treatment reversed the effects of 6-gingerol treatment in SAH rats. These results indicate that 6-gingerol suppressed the expression of GBP2 to activate the PI3K/AKT pathway, improve neurologic outcomes, reduce brain edema and neuronal apoptosis. In summary, our findings suggest that 6-gingerol could attenuate EBI post-SAH in rats, and 6-gingerol may serve as a novel candidate neuroprotective drug for SAH-induced EBI.

Structural and biochemical characterization of an interferon-inducible GTPase, human guanylate binding protein 2 (GBP2)

Structural and biochemical characterization of an interferon-inducible GTPase, human guanylate binding protein 2 (GBP2)

Lower Expression of GBP2 Associated With Less Immune Cell Infiltration and Poor Prognosis in Skin Cutaneous Melanoma (SKCM).

Guanylate binding protein 2 (GBP2) could bind to guanine nucleotides (GMP, GDP, and GTP) and exhibits antiviral activity against influenza virus through the innate immune response. Some researchers have demonstrated that the value of GBP2 in predicting the prognosis of multiple cancers and the complex correlation with immune response. However, the correlation of GBP2 to prognosis and immune cell infiltration level were unknown in skin cutaneous melanoma (SKCM). The GBP2 expression in multiple cancers were evaluated through Tumor Immune Estimation Resource (TIMER) and Oncomine. We also evaluated the influence of GBP2 on overall survival in multiple caners through GEPIA, TIMER, and tissue microarray. The correlation between GBP2 expression level and immune cell or gene markers of immune infiltration level was explored on TIMER and GEPIA. Gene set enrichment analysis was performed using the TCGA dataset. The GBP2 expression level represented a significant reduction and the GBP2 expression was lower compared with the SKCM-Metastasis with P<0.01. Lower GBP2 expression was significantly correlated with the poor overall survival of SKCM patients. Simultaneously, higher GBP2 expression predicted the better SKCM-free survival with P=0.019. GBP2 expression was positively correlated with the infiltration cells of B-cell, CD8+ T-cell, CD4+ T-cell, macrophage, neutrophil, and dendritic cell in SKCM. And there was a significant negative correlation between the expression of GBP2 and DNA methylation in the cBioPortal database (P=3.39e-42). Gene set enrichment analysis revealed that GBP2 was closely correlated with multiple pathways of immune response in cancer. In conclusion, Lower expression of GBP2 associated with less immune cell infiltration and poor prognosis in SKCM and the high promoter methylation of GBP2 represented a promising biomarker for poor prognostication in SKCM.

Guanylate-binding Protein 2 Expression Is Associated With Poor Survival and Malignancy in Clear-cell Renal Cell Carcinoma.

Clear-cell renal cell carcinoma (ccRCC) is a common recalcitrant cancer. However, little is known about biomarkers of ccRCC. In the present study, we investigated the role of guanylate-binding protein 2 (GBP2), an interferon-induced GTPase, in ccRCC and its potential as a biomarker of this disease. GBP2 expression was analyzed using the Gene Expression Omnibus, The Cancer Genome Atlas, and Human Protein Atlas databases. Univariate and multivariate Cox-regression analyses were used to investigate the prognostic value of GBP2 in ccRCC. In addition, quantitative real-time polymerase chain reactions, western blotting, and immunohistochemistry were performed to confirm the expression of GBP2 in tissues from patients with ccRCC who had undergone radical nephrectomy at the Department of Urology, the First Affiliated Hospital of Chongqing Medical University (Chongqing, P. R. China). Cell-function assays were performed to investigate the effect of GBP2 on Caki-1 human kidney-cancer cells. Bioinformatics and in vitro experiments showed that the expression of GBP2 was up-regulated in ccRCC tissues and cells and was positively correlated with the malignant clinicopathological parameters of the disease. Univariate and multivariate Cox-regression analyses showed that GBP2 expression was an independent risk factor for the prognosis of ccRCC. Cell-function assays showed that GBP2 expression promoted the proliferation, migration, and invasion of Caki-1 cells through the WNT/β-catenin signaling pathway. The present results indicate that GBP2 expression may serve as a prognostic biomarker for ccRCC.

GBP2 facilitates the progression of glioma via regulation of KIF22/EGFR signaling

Identifying the mechanism of glioma progression is critical for diagnosis and treatment. Although studies have shown that guanylate-binding protein 2(GBP2) has critical roles in various cancers, its function in glioma is unclear. In this work, we demonstrate that GBP2 has high expression levels in glioma tissues. In glioma cells, depletion of GBP2 impairs proliferation and migration, whereas overexpression of GBP2 enhances proliferation and migration. Regarding the mechanism, we clarify that epidermal growth factor receptor (EGFR) signaling is regulated by GBP2, and also demonstrate that GBP2 interacts directly with kinesin family member 22(KIF22) and regulates glioma progression through KIF22/EGFR signaling in vitro and in vivo. Therefore, our study provides new insight into glioma progression and paves the way for advances in glioma treatment.

Subtyping of microsatellite stability colorectal cancer reveals guanylate binding protein 2 (GBP2) as a potential immunotherapeutic target

BackgroundsProficient-mismatch-repair or microsatellite stability (pMMR/MSS) colorectal cancer (CRC) has limited efficacy for immune checkpoint blockade (ICB) therapy and its underlying mechanism remains unclear. Guanylate binding protein 2 (GBP2) is a...

The Large GTPase, GBP-2, Regulates Rho Family GTPases to Inhibit Migration and Invadosome Formation in Breast Cancer Cells.

Simple SummaryToo many women still die of breast cancer each year. Those breast cancers that kill are those with cells that have migrated away from the primary tumor in the breast and established new tumors at other sites in the body. These tumors are not reached when the original tumor in the breast is removed. This study was designed to determine why some breast cancers move away from their primary tumor and others do not. We have identified a protein that inhibits this movement. Understanding this finding may provide us with ways to inhibit tumor cell movement in patients.Breast cancer is the most common cancer in women. Despite advances in early detection and treatment, it is predicted that over 43,000 women will die of breast cancer in 2021. To lower this number, more information about the molecular players in breast cancer are needed. Guanylate-Binding Protein-2 has been correlated with better prognosis in breast cancer. In this study, we asked if the expression of GBP-2 in breast cancer merely provided a biomarker for improved prognosis or whether it actually contributed to improving outcome. To answer this, the 4T1 model of murine breast cancer was used. 4T1 cells themselves are highly aggressive and highly metastatic, while 67NR cells, isolated from the same tumor, do not leave the primary site. The expression of GBP-2 was examined in the two cell lines and found to be inversely correlated with aggressiveness/metastasis. Proliferation, migration, and invadosome formation were analyzed after altering the expression levels of GBP-2. Our experiments show that GBP-2 does not alter the proliferation of these cells but inhibits migration and invadosome formation downstream of regulation of Rho GTPases. Together these data demonstrate that GBP-2 is responsible for cell autonomous activities that make breast cancer cells less aggressive.

Role of Gate-16 and Gabarap in Prevention of Caspase-11-Dependent Excess Inflammation and Lethal Endotoxic Shock.

Sepsis is a life-threating multi-organ disease induced by host innate immunity to pathogen-derived endotoxins including lipopolysaccharide (LPS). Direct sensing of LPS by caspase-11 activates inflammasomes and causes lethal sepsis in mice. Inhibition of caspase-11 inflammasomes is important for the prevention of LPS-induced septic shock; however, whether a caspase-11 inflammasome-specific suppressive mechanism exists is unclear. Here we show that deficiency of GABARAP autophagy-related proteins results in over-activation of caspase-11 inflammasomes but not of canonical inflammasomes. Gate-16−/−Gabarap−/− macrophages exhibited elevated guanylate binding protein 2 (GBP2)-dependent caspase-11 activation and inflammatory responses. Deficiency of GABARAPs resulted in formation of GBP2-containing aggregates that promote IL-1β production. High mortality after low dose LPS challenge in Gate-16−/−Gabarap−/− mice primed with poly(I:C) or polymicrobial sepsis was ameliorated by compound GBP2 deficiency. These results reveal a critical function of Gate-16 and Gabarap to suppress GBP2-dependent caspase-11-induced inflammation and septic shock.

GBP2 enhances glioblastoma invasion through Stat3/fibronectin pathway.

Guanylate-binding protein 2 (GBP2) is an interferon-inducible large GTPase which is crucial to the protective immunity against microorganisms. However, its biological function in cancer remains largely unknown. Glioblastoma multiforme (GBM) is the most common and deadly brain tumor in adults. Here we show that GBP2 expression is highly elevated in GBM tumor and cell lines, particularly in those of the mesenchymal subtype. High GBP2 expression is associated with poor prognosis. GBP2 overexpression significantly promotes GBM cell migration and invasion in vitro, and GBP2 silencing by RNA interference exhibits opposite effects. We further show that fibronectin (FN1) is dramatically induced by GBP2 expression at both mRNA and protein levels, and FN1 is essential for GBP2-promoted GBM invasiveness. Inhibition of Stat3 pathway prevents GBP2-promoted FN1 induction and cell invasion. Consistently, GBP2 dramatically promotes GBM tumor growth and invasion in mice and significantly reduces the survival time of the mice with tumor. Taken together, these findings establish the role of GBP2/Stat3/FN1 signaling cascade in GBM invasion and suggest GBP2 may serve as a potential therapeutic target for inhibiting GBM invasion.

Plasma GBP2 promoter methylation is associated with advanced stages in breast cancer.

Blood methylated cell-free DNA (cfDNA) as a minimally invasive cancer biomarker has great importance in cancer management. Guanylate binding protein 2 (GBP2) has been considered as a possible controlling factor in tumor development. GBP2 gene expression and its promoter methylation status in both plasma cfDNA and tumor tissues of ductal carcinoma breast cancer patients were analyzed using SYBR green comparative Real-Time RT-PCR and, Methyl-specific PCR techniques, respectively in order to find a possible cancer-related marker. The results revealed that GBP2 gene expression and promoter methylation were inversely associated. GBP2 was down-regulated in tumors with emphasis on triple negative status, nodal involvement and higher cancer stages (p<0.0001). GBP2 promoter methylation on both cfDNA and tumor tissues were positively correlated and was detected in about 88% of breast cancer patients mostly in (Lymph node positive) LN+ and higher stages. Data provided shreds of evidence that GBP2 promoter methylation in circulating DNA may be considered as a possible effective non-invasive molecular marker in poor prognostic breast cancer patients with the evidence of its relation to disease stage and lymph node metastasis. However further studies need to evaluate the involvement of GBP2 promoter methylation in progression-free survival or overall survival of the patients.