CXC chemokine receptor 4 - mediated immune modulation and tumor microenvironment heterogeneity in gastric cancer: Utilizing multi-omics approaches to identify potential therapeutic targets.

IF 5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
BioFactors Pub Date : 2024-10-21 DOI:10.1002/biof.2130
Jing Tang, Wei Wei, Yaoqing Xu, Kexin Chen, Yaping Miao, Weining Fan, Zhi Huang, Jie Liu, Ping Chen, Honghao Luo, Lexin Wang
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引用次数: 0

Abstract

G-protein-coupled receptors (GPRs) are critical regulators of various biological behaviors, and their role in gastric cancer (GC) progression is gaining increasing attention. Among them, the immune regulatory mechanisms mediated by chemokine receptor 4 (CXCR4) remain insufficiently understood. This study aims to explore the immune regulatory functions of CXCR4 and the heterogeneity of the tumor microenvironment (TME) by examining GPR-related gene expression in GC. Through multi-omics approaches, including spatial transcriptomics and single-cell RNA sequencing, we investigated the oncogenic mechanisms of CXCR4, particularly its role in T cell immune exhaustion. In vitro experiments, including ELISA, PCR, CCK8 assays, cell scratch assays, and colony formation assays, were used to validate the role of CXCR4 in the migration and invasion of AGS and SNU-1 cell lines. CXCR4 silencing using siRNA further demonstrated its regulatory effects on these cellular processes. Our results revealed a strong correlation between elevated CXCR4 expression and increased exhaustion of regulatory T cells (Tregs) in the TME. Furthermore, heightened CXCR4 expression was linked to increased TME heterogeneity, driven by oxidative stress and activation of the NF-κB pathway, promoting immune evasion and tumor progression. Silencing CXCR4 significantly inhibited the invasive and proliferative abilities of AGS and SNU-1 cells, while also reducing the expression of pro-inflammatory cytokines IL-1β and interleukin-6, thus alleviating chronic inflammation and improving TME conditions. In conclusion, our comprehensive investigation highlights CXCR4 as a key mediator of TME dynamics and immune modulation in GC. Targeting CXCR4 presents a promising therapeutic strategy to slow tumor progression by reducing Tregs-mediated immune exhaustion and TME heterogeneity, positioning it as a novel therapeutic target in GC treatment.

胃癌中由 CXC 趋化因子受体 4 介导的免疫调节和肿瘤微环境异质性:利用多组学方法确定潜在的治疗靶点。
G 蛋白偶联受体(GPRs)是各种生物行为的关键调节因子,它们在胃癌(GC)进展中的作用正日益受到关注。其中,趋化因子受体 4(CXCR4)介导的免疫调节机制仍未得到充分了解。本研究旨在通过检测 GC 中 GPR 相关基因的表达,探索 CXCR4 的免疫调节功能和肿瘤微环境(TME)的异质性。通过空间转录组学和单细胞RNA测序等多组学方法,我们研究了CXCR4的致癌机制,尤其是它在T细胞免疫衰竭中的作用。体外实验包括 ELISA、PCR、CCK8 试验、细胞划痕试验和集落形成试验,用于验证 CXCR4 在 AGS 和 SNU-1 细胞系的迁移和侵袭中的作用。使用 siRNA 沉默 CXCR4 进一步证明了它对这些细胞过程的调控作用。我们的研究结果表明,CXCR4 表达的升高与 TME 中调节性 T 细胞(Tregs)衰竭的增加密切相关。此外,CXCR4表达的升高与TME异质性的增加有关,氧化应激和NF-κB通路的激活促进了免疫逃避和肿瘤进展。沉默 CXCR4 能显著抑制 AGS 和 SNU-1 细胞的侵袭和增殖能力,同时还能减少促炎细胞因子 IL-1β 和白细胞介素-6 的表达,从而缓解慢性炎症并改善 TME 的状况。总之,我们的综合研究强调了 CXCR4 是 GC 中 TME 动态和免疫调节的关键介质。靶向 CXCR4 可减少 Tregs 介导的免疫耗竭和 TME 的异质性,从而减缓肿瘤的进展,是一种很有前景的治疗策略,可作为治疗 GC 的新靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
BioFactors
BioFactors 生物-内分泌学与代谢
CiteScore
11.50
自引率
3.30%
发文量
96
审稿时长
6-12 weeks
期刊介绍: BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.
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