Abstract

Recent evidence shows that v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets1) is implicated in tumor development and progression. However, the clinical potentials and underlying mechanisms of Ets1 in gastric cancer progression and metastasis remain largely unknown. In this study, Ets1 immunostaining was identified in 56 of 84 (66.7%) gastric cancer tissues, which was correlated with tumor invasion and metastasis. In gastric cancer specimens and cell lines, miRNA-145 (miR-145) was downregulated and inversely correlated with Ets1 expression. Bioinformatics analysis and luciferase reporter assay revealed that miR-145 directly targeted the 3'-untranslated region (3'-UTR) of Ets1 mRNA. Overexpression or knockdown of miR-145 responsively altered both the mRNA and protein levels of Ets1 and its downstream genes, matrix metalloproteinase (MMP-1)-1 and -9, in gastric cancer cell lines SGC-7901 and MKN-45. Ectopic expression of miR-145 suppressed the invasion, metastasis, and angiogenesis of SGC-7901 and MKN-45 cells in vitro and in vivo. In addition, the effects of miR-145 on Ets1 expression, migration, invasion, and angiogenesis were rescued by restoration of Ets1 expression in these cells. Furthermore, anti-miR-145 inhibitor promoted the migration, invasion, and angiogenesis, whereas siRNA-mediated Ets1 knockdown phenocopied the effects of miR-145 overexpression in gastric cancer cells. These results show that miR-145 suppresses Ets1 expression via the binding site in the 3'-UTR, thus inhibiting the invasion, metastasis, and angiogenesis of gastric cancer cells.

Highlights

  • Gastric cancer is the fourth most common cancer in humans, and its prognosis still remains poor due to the invasion and metastasis [1]

  • Better elucidating the mechanisms of metastasis is important for improving the therapeutic efficiencies of gastric cancer [1, 2]. v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets1) is a member of the Ets transcription factor family that participates in the migration, invasion, and angiogenesis of cancer cells [3]

  • We explored the roles of miR-145 in the invasion, metastasis, and angiogenesis of gastric cancer cells

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Summary

Introduction

Gastric cancer is the fourth most common cancer in humans, and its prognosis still remains poor due to the invasion and metastasis [1]. The metastatic process of cancer cells is complicated and consists of multiple steps, including detachment, local invasion, motility, angiogenesis, extravasation, and growth in distant organs [2]. Better elucidating the mechanisms of metastasis is important for improving the therapeutic efficiencies of gastric cancer [1, 2]. V-ets erythroblastosis virus E26 oncogene homolog 1 (Ets1) is a member of the Ets transcription factor family that participates in the migration, invasion, and angiogenesis of cancer cells [3]. The mechanisms underlying Ets expression in cancers still remain largely unknown

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