Tristetraprolin inhibits gastric cancer progression through suppression of IL-33.

Kaiyuan Deng,Jiazeng Xia,Yigang Chen,Qin Zhao,Hao Wang,Ting Shan,Hong Zhou

doi:10.1038/srep24505

Abstract

Tristetraprolin (TTP) is an adenine/uridine (AU)-rich element (ARE)-binding protein that can induce degradation of mRNAs. In this study, we report that TTP suppresses the expression of interleukin-33 (IL-33), a tumor-promoting inflammatory cytokine, and thereby inhibits the progression of gastric cancer (GC). Overexpression of TTP decreased the level of IL-33, whereas knockdown of TTP increased IL-33 levels. We also discovered that TTP inhibited the proliferation, migration, and invasion of GC cell lines through regulation of IL-33. Furthermore, TTP RNA and protein levels were remarkably reduced in GC and inversely correlated with IL-33 level, and they were also closely associated with depth of invasion, lymph node metastasis, advanced TNM stage, as well as survival rate. Taken together, these findings identified TTP as a downregulator of IL-33, and further suggest that TTP can serve as a novel biomarker for the diagnosis of GC and as a potential therapeutic target for GC treatment.

Highlights

Gastric cancer (GC) is one of the most common cancers and the second leading cause of cancer-related death globally, with an estimated 951,600 new cases and 723,100 deaths occurring in 20121
TTP mRNA levels in different cell lines were determined by quantitative real-time PCR (qRT-PCR), and the levels of TTP mRNA were lower in MGC-803 (P = 0.001) and BGC-823 (P = 0.002) cell lines, compared with those in an immortalized human gastric epithelial cell line (GES-1)
An representative example is associated with human gastric cancer, where inflammation caused by the bacterium Helicobacter pylori remains a major risk factor for cancer development[22,23]

Summary

Introduction

Gastric cancer (GC) is one of the most common cancers and the second leading cause of cancer-related death globally, with an estimated 951,600 new cases and 723,100 deaths occurring in 20121. Pro-inflammatory cytokines, such as interleukins, have been reported to be up-regulated and correlated with worse prognosis in GC4. Elevated levels of IL-33 have been discovered in both sera and tumor tissues of GC patients, facilitating GC progression by inducing cell invasion and migration[11,12]. The mRNAs of many pro-inflammatory cytokines are found to be unstable[13] The stability of these mRNAs is mainly determined by the AU-rich elements (AREs) within their 3′ untranslated regions (3′ UTR), which may induce mRNA destabilization and degradation through binding to specific proteins[14,15]. Tristetraprolin (TTP) is a well-known ARE-binding protein that is involved in post-transcriptional regulation of many pro-inflammatory cytokines and transcription factors, such as IL-23, IL-6, HIF-1α and E2F1. Our study reveals a tumor-suppressive role for TTP in GC, and indicates the potential application of TTP for treating IL-33-mediated tumor promotion

Methods

Results

Conclusion