GATA6 suppresses migration and metastasis by regulating the miR-520b/CREB1 axis in gastric cancer
GATA6 suppresses migration and metastasis by regulating the miR-520b/CREB1 axis in gastric cancer
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GATA6通过调节miR-520b/CREB1轴抑制胃癌迁移和转移
DOI：
10.1038/s41419-018-1270-x
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发表时间：
2019-01-15
影响因子：
9
通讯作者：
Zhao, Xiaodi
中科院分区：
文献类型：
--
作者：
Liu, Hao;Du, Feng;Zhao, Xiaodi
转录因子（Transcription factors，TF）和微小RNA（microRNAs，miRNAs）在肿瘤的发生、发展过程中密切相关，但它们在胃癌转移中的相互作用尚不清楚。在这里，我们报告了一种新的抑制作用，GATA 6在抑制胃癌转移的反式激活miR-520 b。我们发现，GATA 6的表达在转移性胃癌细胞和组织中显著下调，其下调与胃癌预后不良相关。GATA 6过表达抑制胃癌细胞的迁移、侵袭和转移。荧光素酶报告基因分析和染色质免疫沉淀分析表明，miR-520 b是GATA 6的直接转录靶点。胃癌组织中miR-520 b的表达与GATA 6的表达呈正相关，miR-520 b的异位表达可抑制胃癌细胞的迁移和侵袭。此外，cAMP反应元件结合蛋白1（CREB 1）被鉴定为miR-520 b的直接和功能性靶点，并且GATA 6可以通过miR-520 b介导的CREB 1抑制GC细胞的迁移和转移。GATA 6和miR-520 b的下调可能是CREB 1在胃癌中过度表达的部分原因。总之，我们的研究结果提供了新的见解TF-miRNA调控网络参与胃癌转移。靶向GATA 6/miR-520 b/CREB 1轴可能是治疗GC的有效方法。
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.