IRF6 Is Directly Regulated by ZEB1 and ELF3, and Predicts a Favorable Prognosis in Gastric Cancer.

Dandan Li,Xuemei Qiu,Shanshan Qin,Li Xu,Xudong Zhang,Ping Cheng,Jingjie Wang,Ying Liu

doi:10.3389/fonc.2019.00220

Abstract

Interferon regulatory factor 6 (IRF6) acts as a tumor suppressor and controls cell differentiation in ectodermal and craniofacial tissues by regulating expression of target genes. However, its function in gastric cancer (GC) remains unknown to date. In this study, we found that the IRF6 expression was significantly downregulated in GC. And the decreased expression of IRF6 was clinically correlated with poor prognosis of GC. Moreover, loss-of-function and gain-of-function studies showed that IRF6 was negatively regulated by ZEB1 but positively regulated by ELF3. Additionally, transcription factor ZEB1 and ELF3 could directly bind on IRF6 promoter, which suggested that transcription factor IRF6 is transcriptionally regulated by ZEB1 and ELF3. Nevertheless, we found that IRF6 expression was negatively related to its promoter methylation in TCGA stomach cancer cohorts. The downregulation of IRF6 in GC might be due to the overexpression of ZEB1 and the DNA methylation of IRF6 promoter.

Highlights

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide, especially in East Asia [1]
The results showed that the transcripts level of Interferon regulatory factor 6 (IRF6) in the gastric cancer tissues was lower than in the corresponding normal tissues (Figure 1B)
In order to understand the significance of decreased IRF6 expression in gastric cancer, we further determined the potential associations between IRF6 expression level and clinicopathological features in GSE62254 GC cohorts (n = 300)

Summary

Introduction

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide, especially in East Asia [1]. There is a great advancement on the gastric carcinogenesis, the molecular mechanisms underlying GC progression remains unclear [4]. Better understanding of the GC progression is essential to identify new effective diagnostic markers and novel effective therapies for GC patients. Unlike other IRF family members, IRF6 is not involved in IFN gene regulation, but instead have an essential role in skin development and keratinocyte differentiation [6, 7]. Recent studies have proved that IRF6, regulated by TP63, plays a tumor suppressor role in squamous cell carcinomas through a Notch-dependent mechanism [8,9,10]. The IRF6 gene expression regulation in gastrointestinal cancer types are not yet reported

Methods

Results

Conclusion