Non-tumor tissue derived interleukin-17B activates IL-17RB/AKT/β-catenin pathway to enhance the stemness of gastric cancer.

Qingli Bie,Huaxi Xu,Dong Zheng,Aihua Gong,Shengjun Wang,Caixia Sun,Qi Guo,Yumin Wu,Zhaoliang Su,Xiaoyun Ji,Chunye Li

doi:10.1038/srep25447

Abstract

Inflammation is a critical component involved in tumor progression. Interleukin-17 (IL-17) belongs to a relatively new family of cytokines that has been associated with the progression of cancers. However, the role of IL-17B/IL-17RB (IL-17 receptor B) signaling to stemness of gastric cancer remains unknown. Here, we confirmed that the expression of IL-17RB in gastric cancer tissues was significantly increased, that overexpression was associated with poor prognosis of gastric cancer patients, and that overexpression was positively correlated with some stemness markers. Interestingly, the expression of IL-17B was upregulated in patient serum rather than gastric tumor tissues. Furthermore, exogenous rIL-17B significantly promoted the stemness of gastric cancer cells depending on IL-17RB and induced the expression of IL-17RB. Simultaneously, the expression of phosphorylated AKT, GSK-3β, and β-catenin as well as the nuclear translocation of β-catenin were significantly increased in the MGC-803 cell in a dose-dependent manner, when treated with rIL-17B. The AKT inhibitor, LY294002, and the knockdown of AKT expression reversed the rIL-17B-induced upregulation of β-catenin and some stemness markers. Together, our results indicate that the IL-17B/IL-17RB signal can promote the growth and migration of tumor cells, and upregulate cell stemness through activating the AKT/β-catenin pathway in gastric cancer, suggesting that IL-17RB may be a novel target in human gastric cancer therapy.

Highlights

Gastric cancer is the fourth most common cancer and second leading cause of death from malignancy worldwide[1]
In order to explore the role of IL-17RB in gastric cancer, we evaluated the expression of IL-17RB protein in paired non-cancerous and gastric cancer tissues by western blot analysis
Immunofluorescence staining indicated that the IL-17RB protein was predominantly expressed on the membrane of cancer cells, and that it was found in significantly higher levels in gastric cancer tissues (Fig. 1c)

Summary

Introduction

Gastric cancer is the fourth most common cancer and second leading cause of death from malignancy worldwide[1]. Wen-Hwa and co-workers first reported that amplified IL-17B/IL-17RB signaling promotes breast cancer tumorigenicity by activating nuclear factor-kB, to upregulate the antiapoptotic factor Bcl-214. The Wnt/β -catenin signaling pathway has been implicated in the maintenance of self-renewal in various types of stem cells[17,18] Abnormal activation of this signaling correlates with tumorigenesis and progression by maintaining cancer stem cells (CSCs), and plays a key role in the self-renewal of gastric CSCs19,20. Xiang et al demonstrated that IL-17 produced by T-helper (Th17) cells and macrophages play important roles in promoting the self-renewal of ovarian CD133 (+) cancer stem-like cells (CSLCs) by activating the nuclear factor (NF)-κ B and the p38 mitogen-activated protein kinase (MAPK) signaling pathway[21]. The precise contribution of IL-17B/IL-17RB signaling in maintaining CSCs remains unclear

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Conclusion