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

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.

Expression patterns of seven key genes, including β-catenin, Notch1, GATA6, CDX2, miR-34a, miR-181a and miR-93 in gastric cancer

“…In accordance with our study, Liu et al reported that the expression of GATA6 was significantly decreased in metastatic GC cells and tissues. In addition, they found that overexpression of GATA6 inhibited GC cell migration, invasion and metastasis in vitro and in vivo 65 . www.nature.com/scientificreports/ In contrast with our findings, Sulahian et al reported that GATA6 gene is amplified or overexpressed in gastric, esophageal and pancreatic adenocarcinomas.…”

“…In accordance with our study, Liu et al reported that the expression of GATA6 was significantly decreased in metastatic GC cells and tissues. In addition, they found that overexpression of GATA6 inhibited GC cell migration, invasion and metastasis in vitro and in vivo 65 .…”

Multiple roles and regulatory mechanisms of the transcription factor GATA6 in human cancers

“…However, the interaction of the two in GC transfer remains undetermined. In a recent study on GC, overexpression of GATA6 inhibits GC cell migration, invasion and metastasis in vitro and in vivo by inhibiting miR‐520b‐mediated cAMP responsive element‐binding protein 1 (CREB1) . Targeting the GATA6/miR‐520b/CREB1 axis may be an effective method for GC treatment.…”

“…In a recent study on GC, overexpression of GATA6 inhibits GC cell migration, invasion and metastasis in vitro and in vivo by inhibiting miR-520bmediated cAMP responsive element-binding protein 1 (CREB1). 59 Targeting the GATA6/miR-520b/CREB1 axis may be an effective method for GC treatment. In addition, activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) (JAK/STAT) signal plays a key role in GC development.…”

Loss of GATA6 expression promotes lymphatic metastasis in bladder cancer

“…Although high expression of GATA6 was found in several types of cancer, GATA6 was downregulated and played tumor-suppressive roles by inhibiting cell proliferation, migration, invasion, epithelial-mesenchymal transition, stem cell-like properties, and metastasis in pancreatic, lung, liver, ovarian, and gastric cancers. 23,[26][27][28][29][30] However, the role of GATA6 in bladder cancer remains unknown.…”