GATA6 suppresses migration and metastasis by regulating the miR-520b/CREB1 axis in gastric cancer

Hao Liu,Qingfeng Wu,Xin Wang,Daiming Fan,Feng Du,Yuanyuan Lu,Xiaodi Zhao,Xiaoliang Gao,Mingfu Tong,Jiayi Cao,Lina Sun,Qi Wang,Yongzhan Nie,Jian Wu,Tianyu Cao,Nan Wu

doi:10.1038/s41419-018-1270-x

Abstract

Transcription factors (TFs) and microRNAs (miRNAs) are tightly linked to each other in tumor development and progression, but their interactions in gastric cancer (GC) metastasis remain elusive. Here we report a novel suppressive role of GATA6 in inhibiting GC metastasis by transactivating miR-520b. We found that GATA6 expression was significantly downregulated in metastatic GC cells and tissues and that its downregulation was correlated with a poor GC prognosis. Overexpression of GATA6 suppressed GC cell migration, invasion and metastasis both in vitro and in vivo. Luciferase reporter assays and chromatin immunoprecipitation assays demonstrated that miR-520b is a direct transcriptional target of GATA6. Moreover, miR-520b expression was positively correlated with GATA6 expression in GC tissues, and ectopic expression of miR-520b inhibited the migration and invasion of GC cells. Furthermore, cAMP responsive element binding protein 1 (CREB1) was identified as a direct and functional target of miR-520b, and GATA6 could suppress GC cell migration and metastasis via miR-520b-mediated repression of CREB1. Downregulation of GATA6 and miR-520b may partly account for the overexpression of CREB1 in GC. In conclusion, our results provide novel insight into the TF-miRNA regulatory network involved in GC metastasis. Targeting the GATA6/miR-520b/CREB1 axis may be an effective approach for GC treatment.

Highlights

The incidence and mortality of gastric cancer (GC) have decreased in recent years, GC still poses a tremendous threat to human health, being the fourth most common cancer and the second leading cause of cancer-related death worldwide[1]
GATA6 is downregulated in metastatic GC cells and tissues To explore the potential role of GATA6 in GC metastasis, we first examined its expression in tissue microarrays containing samples from 34 cases of lymph node metastases, 55 cases of GC and paired adjacent nontumor tissues
Immunohistochemistry (IHC) results showed that GATA6 was primarily localized in the nucleus of glandular cells from the bottom to the top of the normal stomach epithelium and was significantly downregulated in metastatic GC tissues compared with primary GC tissues and adjacent nontumor tissues (Fig. 1A, B)

Summary

Introduction

The incidence and mortality of gastric cancer (GC) have decreased in recent years, GC still poses a tremendous threat to human health, being the fourth most common cancer and the second leading cause of cancer-related death worldwide[1]. Because GC patients in the early stage are often asymptomatic, most are diagnosed at an advanced stage with tumor metastasis, which. GATA6 belongs to a family of zinc finger-containing transcription factors (TFs) that bind to the (A/T) GATA (A/G) consensus sequence[3]. As a lineage-restricted transcription factor, GATA6 plays an important role in embryogenesis, cell differentiation, the regulation of tissue-specific genes, and carcinogenesis[4,5]. Recent studies have indicated that GATA6 plays important roles in tumor metastasis. In pancreatic ductal adenocarcinoma (PDAC), GATA6 suppresses metastasis by inhibiting the epithelial–mesenchymal transition (EMT) both directly and indirectly[6]. In a subset of high-grade lung adenocarcinoma and metastatic cancer cells, GATA6 expression is decreased, and recovery of its function can reduce metastasis[7].

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Results

Conclusion