H. pylori infection induces CXCL8 expression and promotes gastric cancer progress through downregulating KLF4

Abstract

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.

Helicobacter pylori with trx1 high expression promotes gastric diseases via upregulating the IL23A/NF‐κB/IL8 pathway

“…[22][23][24][25][26][27] Previous studies have shown that IL6 activates signal transducers to enhance cell growth and IL8 promotes proliferation and migration of gastric cancer cells. 28,29 By analyzing the differential Studies have shown that the expression of IL23A and IL17A in CD4 + T cells can be significantly enhanced after H. pylori infection. 30 Vitro experiments have shown that IL23A can induce the activation of IL17A/IL17RA/NF-κB after stimulation with H. pylori, thus promoting the proliferation of gastric cancer cells.…”

GHRL as a Prognostic Biomarker Correlated With Immune Infiltrates and Progression of Precancerous Lesions in Gastric Cancer

“…Additionally, this study discovered that GHRL was related to immune in ltration in GC. In the tumor microenvironment, it has been demonstrated that immune cell in ltration played vital roles in the development and progression of cancer [35,36] . GHRL played a role in in ammatory and immune responses [37] .…”

Krüppel-like factors in tumors: Key regulators and therapeutic avenues

“…The promoter region of the CXC ligand-8 (CXCL8) gene contains KLF4 binding sites, and the inactivation of KLF4 in gastric cancer tissues resulted in significant upregulation of the CXCL8 expression. By chemotactic bone marrow-derived suppressor cells, CXCL8 inhibits the activation of T cells and contributes to the immunosuppression of TME ( 190 ). Similarly, KLF5 mediates CXCL12 expression, creating an immunosuppressive microenvironment in tumor tissue and thus reducing the efficacy of immunotherapy ( 191 ).…”