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

Zhengxia Liu,Wenting Xu,Xiao Wu,Yakun Liu,Siyuan Qiao,Wanchun Zhang,Siying Wang,Yuanyuan Tian

doi:10.1002/mc.23309

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.

Highlights

Tumour-derived C-X-C motif chemokine ligand 8 (CXCL8) facilitates the movement of myeloid-derived suppressor cells (MDSCs), which have the capacity to restrain antitumour immune responses, into the tumour microenvironment
We found that the expression levels of CXCL8 and Kruppel-like factor 4 (KLF4) were altered in human gastric cancer (GC) tissues compared to normal gastric tissues in opposite ways
Taken together, our findings demonstrate that CXCL8 is a decisive downstream target gene of KLF4 in gastric carcinoma

Summary

Introduction

Tumour-derived CXCL8 facilitates the movement of myeloid-derived suppressor cells (MDSCs), which have the capacity to restrain antitumour immune responses, into the tumour microenvironment. Gastric cancer remains a crucial cancer worldwide, as it ranks as the third leading cause of malignant cancer death and the fifth most frequently diagnosed cancer [1]. H. pylori-associated cytotoxin-associated gene A (CagA) protein, which is transferred to gastric epithelial cells via bacterial type IV secretion, is an oncoprotein that can cause malignant neoplasms in mammals [1, 4]. A large number of studies have shown that H. pylori promotes the progression, metastasis and recurrence of GC [5, 6]. This finding may be closely related to the persistence of H. pylori infection, which generates a local immunosuppressive microenvironment, allowing GC cells to escape immune surveillance [7]

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Conclusion