Tumour-derived CXCL8 facilitates the movement of myeloid-derived suppressor cells, which are able to restrain antitumour immune responses to the tumour microenvironment. Kruppel-like factor 4 (KLF4) is a potential tumour suppressor in gastric cancer (GC). However, knowledge regarding correlations between KLF4 and CXCL8 in GC is limited. We use cellular and molecular biological methods to assess whether these two factors interact in GC. Expression CXCL8 and KLF4 was altered in human GC tissues compared to normal gastric tissues in opposite ways. Additionally, cytotoxin-associated gene A protein (CagA) gene transduction or Helicobacter pylori (H. pylori) infection upregulated CXCL8 expression. Knockdown of KLF4 expression increased CXCL8 protein and RNA expression, whereas its overexpression had the opposite effect. CXCL8-mediated enhancement of GC cell migration and proliferation was reversed by upregulation of KLF4 expression. Further mechanistic research revealed that KLF4 binds the CXCL8 promoter, suppressing CXCL8 transcription. Moreover, CXCL8 stimulation reduced KLF4 protein expression and promoted GC cell proliferation and migration, eventually promoting neoplasm growth in vivo. Together, our findings demonstrate that CagA promotes CXCL8 and inhibits KLF4. CXCL8 is a decisive downstream target gene of KLF4, and KLF4 negatively regulates CXCL8 in GC. Furthermore, CXCL8's negative regulation of KLF4 in vivo and in vitro, indicates that CagA may downregulate KLF4 by inducing CXCL8 expression, low expression of KLF4 further promotes that of CXCL8, forming a vicious circle in GC. Targeted KLF4 activation might improve the immunosuppressive microenvironment through direct negative regulation of CXCL8, providing a new potential target to strengthen the efficacy of immunotherapy in GC patients.

中文翻译：

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H. pylori 感染通过下调 KLF4 诱导 CXCL8 表达并促进胃癌进展

肿瘤来源的 CXCL8 促进骨髓来源的抑制细胞的运动，这些细胞能够抑制对肿瘤微环境的抗肿瘤免疫反应。Kruppel 样因子 4 (KLF4) 是胃癌 (GC) 的潜在肿瘤抑制因子。然而，关于 GC 中 KLF4 和 CXCL8 之间相关性的知识是有限的。我们使用细胞和分子生物学方法来评估这两个因素在 GC 中是否相互作用。与正常胃组织相比，人类 GC 组织中 CXCL8 和 KLF4 的表达以相反的方式发生了改变。此外，细胞毒素相关基因 A 蛋白 (CagA) 基因转导或幽门螺杆菌 ( H. pylori) 感染上调 CXCL8 表达。KLF4 表达的敲低增加了 CXCL8 蛋白和 RNA 的表达，而其过表达则具有相反的效果。CXCL8 介导的 GC 细胞迁移和增殖的增强被 KLF4 表达的上调逆转。进一步的机制研究表明，KLF4 结合 CXCL8 启动子，抑制 CXCL8 转录。此外，CXCL8 刺激降低 KLF4 蛋白表达并促进 GC 细胞增殖和迁移，最终促进体内肿瘤生长。总之，我们的研究结果表明 CagA 促进 CXCL8 并抑制 KLF4。CXCL8 是 KLF4 的决定性下游靶基因，KLF4 在 GC 中负调控 CXCL8。此外，CXCL8 在体内和体外对 KLF4 的负调节，表明 CagA 可能通过诱导 CXCL8 表达下调 KLF4，KLF4 的低表达进一步促进 CXCL8 的表达，在 GC 中形成恶性循环。靶向 KLF4 激活可能通过对 CXCL8 的直接负调节来改善免疫抑制微环境，为加强 GC 患者免疫治疗的疗效提供了一个新的潜在靶点。