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

Abstract

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 <i>GBP5</i> in GC cell progression. Potential oncogenic roles of <i>GBP5</i> 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 <i>GBP5</i> in GC. Downstream targets of <i>GBP5</i> were identified using RNA-sequencing analysis and verified using western blotting or quantitative polymerase chain reaction analysis in different cell lines. <i>GBP5</i> expression is commonly upregulated and promotes the proliferation and migration of GC cells. Mechanistically, <i>GBP5</i> was regulated by the IFNγ-Janus kinase (JAK1)-signal transducer and activator of transcription 1 (STAT1) axis and induced CXCL8 expression. Interestingly, <i>GBP5</i>-induced CXCL8 regulated the <i>JAK1-STAT1</i> signaling pathway to form a positive feedback loop. Moreover, <i>GBP5</i> is closely related to the TIME and may be used as a biomarker for predicting the efficacy of immunotherapy. Our findings revealed a new <i>JAK1-STAT1/GBP5/CXCL8</i> pathway and highlighted the value of <i>GBP5</i> as a predictive biomarker and novel target for GC intervention.