G6PD-NF-κB-HGF Signal in Gastric Cancer-Associated Mesenchymal Stem Cells Promotes the Proliferation and Metastasis of Gastric Cancer Cells by Upregulating the Expression of HK2.

Bin Chen,Zhihong Chen,Qianqian Wang,Shuwei Guo,Tuo Cai,Rongman Xu,Zhiqiang Han,Li Sun,Wenrong Xu,Bo Shen,Mei Wang,Wei Zhu,Xueyan Zang,Chao Huang,Yuanyuan Zhao

doi:10.3389/fonc.2021.648706

Abstract

Background: Tumor-associated stromal cells have been widely recognized for their tumor-promoting capability involving paracrine signaling. However, the underlying mechanism and the effects of the molecules in the glycolysis pathway in gastric cancer-associated mesenchymal stem cells (GCMSCs) and gastric cancer cells on tumor progression remain unclear.Methods: The expression of hepatocyte growth factor (HGF) in GCMSCs and bone marrow mesenchymal stem cells (BMMSCs) was detected by enzyme-linked immunosorbent assay (ELISA). The effect of HGF derived from GCMSCs on the proliferation, metastasis, and HK2 expression of gastric cancer cells was evaluated in vitro and in vivo. The effects of G6PD on the production of HGF in mesenchymal stem cells (MSCs) were analyzed by immunoblotting.Results: HGF derived from GCMSCs promoted glycolysis, proliferation, and metastasis of gastric cancer by upregulating c-Myc-HK2 signal. The progression of the disease induced by GCMSCs decelerated in the absence of HK2. The expression of G6PD activated NF-κB signaling and stimulated the production of HGF in GCMSCs. Blocking HGF derived from GCMSCs decreased proliferation, metastasis, and angiogenesis of gastric cancer cells in vivo.Conclusions: GCMSCs highly expressed G6PD and facilitated the progression of gastric cancer through the G6PD-NF-κB-HGF axis coordinates. Blocking HGF derived from GCMSCs is a potential new therapeutic target for the treatment of gastric cancer.

Highlights

Gastric carcinoma, which is a type of digestive system tumors, is associated with high morbidity and mortality [1]
We found that Glucose-6-phosphate dehydrogenase (G6PD)-NF-κB signaling in gastric cancer mesenchymal stem cells (GCMSCs) facilitated the production of HGF, which could activate the MET receptor
We hypothesized that GCMSCs functioned as regulators of the tumor metabolism in the tumor microenvironment

Summary

Introduction

Gastric carcinoma, which is a type of digestive system tumors, is associated with high morbidity and mortality [1]. Due to the importance of the Warburg effect on tumor progression, further understanding of the biology of the stromal and tumor cells is essential. Previous work, including our own, has demonstrated that tumor mesenchymal stem cells (MSCs), which belong to stromal cells in the tumor microenvironment, can promote tumor development through paracrine signaling [3,4,5,6]. MSCs differ from gastric cancer mesenchymal stem cells (GCMSCs) in cytokine production [7]. As G6PD is highly expressed in gastric cancer tissues, it is speculated that it plays a key role in regulating cytokine production. The underlying mechanism and the effects of the molecules in the glycolysis pathway in gastric cancer-associated mesenchymal stem cells (GCMSCs) and gastric cancer cells on tumor progression remain unclear

Methods

Results

Conclusion