Cao Feng-Yu, Wang Chen-Hong, Li Xiang, Ma Ming-Zhen, Tao Gong-Cai, Yang Chao, Li Kai, He Xiao-Bo, Tong Shi-Lun, Zhao Qing-Chuan, Su Song, Song Dan, Zheng Yong-Bin
Department of Gastrointestinal Surgery, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University Wuhan 430000, Hubei, China.
State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University Xi'an 710032, Shaanxi, China.
Am J Cancer Res. 2023 Apr 15;13(4):1310-1328. eCollection 2023.
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 in GC cell progression. Potential oncogenic roles of 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 in GC. Downstream targets of were identified using RNA-sequencing analysis and verified using western blotting or quantitative polymerase chain reaction analysis in different cell lines. expression is commonly upregulated and promotes the proliferation and migration of GC cells. Mechanistically, was regulated by the IFNγ-Janus kinase (JAK1)-signal transducer and activator of transcription 1 (STAT1) axis and induced CXCL8 expression. Interestingly, -induced CXCL8 regulated the signaling pathway to form a positive feedback loop. Moreover, is closely related to the TIME and may be used as a biomarker for predicting the efficacy of immunotherapy. Our findings revealed a new pathway and highlighted the value of as a predictive biomarker and novel target for GC intervention.
鸟苷酸结合蛋白5（GBP5）是干扰素（IFN）诱导的大GTP酶家族成员，可调节细胞自主免疫和恶性肿瘤转化。然而，GBP5在胃癌（GC）中的具体作用和潜在机制仍不清楚。在本研究中，我们旨在确定GBP5在GC细胞进展中的作用及其潜在机制。使用生物信息学分析全面评估GBP5在GC中的潜在致癌作用及其与肿瘤免疫微环境（TIME）的关系。使用免疫组织化学评估GBP5的蛋白表达水平及其与患者临床病理特征的相关性。此外，进行了多种体外功能实验以确定GBP5在GC中的功能。使用RNA测序分析鉴定GBP5的下游靶点，并在不同细胞系中使用蛋白质免疫印迹或定量聚合酶链反应分析进行验证。GBP5表达通常上调并促进GC细胞的增殖和迁移。机制上，GBP5受IFNγ- Janus激酶（JAK1）-信号转导子和转录激活子1（STAT1）轴调控并诱导CXCL8表达。有趣的是，GBP5诱导的CXCL8调节GBP5信号通路以形成正反馈回路。此外，GBP5与TIME密切相关，可用作预测免疫治疗疗效的生物标志物。我们的研究结果揭示了一条新的GBP5通路，并突出了GBP5作为预测生物标志物和GC干预新靶点的价值。
