A reciprocal feedback of miR-548ac/YB-1/Snail induces EndMT of HUVECs during acidity microenvironment

Jingyuan Chen,Yuhang Hu,Ping Hu,Hewei Xiong,Gang Zhao,Shengbo Han,Fengyu Xu,Jinhuang Chen,Zhu Zeng,Ya Zhang,Zunxiang Ke

doi:10.1186/s12935-021-02388-8

Abstract

BackgroundResearches indicated the process of Endothelial-Mesenchymal-Transition (EndMT) of vascular endothelial cells (ECs) was critically involved in the progression of tumor. ECs demonstrated functional and phenotypic heterogeneity when located under different microenvironments. The extracellular pH of tumor tissues was acidic compared to that of normal tissues. However, there was still unclear whether the acidic microenvironment affected the EndMT of vascular ECs.MethodsHuman Umbilical Vein Endothelial Cell (HUVECs) was cultured under the normal or acidic medium to evaluate the alteration of morphology, migration, permeability, and EndMT markers. Microarray assay was adopted to analyze the differential expression of miRNAs in the acidity-treated HUVECs. Gain- and loss- of function experiments were performed to evaluate the functional role of miRNA-548ac on acidity-induced EndMT of HUVECs. Luciferase reporter and Chromatin-immunoprecipitation assays were conducted to assess the downstream pathway of miRNA-548ac in acidity-induced EndMT of HUVECs.ResultsOur results showed that HUVECs demonstrated mesenchymal transition under acidic conditions with the increase of migration, permeability, and expression of α-SMA and Vimentin, but the expression of vascular endothelial cadherin (VE-cadherin) and CD31 were reduced. In addition, the acidity-treated HUVECs remarkably facilitated the transmigration of pancreatic cancer cells. The expression of miRNA-548ac was significantly decreased in the acidity-treated HUVECs. Moreover, overexpression of miR-548ac inhibited the EndMT of HUVECs and consequently impeded the transmigration of pancreatic cancer cells. The miR-548ac inhibited the expression of YB-1 by binding to the 3’UTR of its mRNA, and YB-1 promoted the translation of Snail which was a critical regulator of EndMT. What’s more, Snail transcriptionally inhibited the expression of miR-548ac through binding to the promoter of its host gene.ConclusionsOur data implicated that the acidic microenvironment promoted the EndMT of HUVECs by the miR-548ac/YB-1/Snail axis, which could contribute to the metastasis of pancreatic cancer.

Highlights

Researches indicated the process of Endothelial-Mesenchymal-Transition (EndMT) of vascular endothelial cells (ECs) was critically involved in the progression of tumor
Acidity induces EndMT of human umbilical vein vascular endothelial cells (HUVECs) To explore the effect of acidic p He on endothelial cells (ECs), HUVECs were incubated in normal or different acidic mediums
Acidity‐induced EndMT promotes the permeability of HUVECs Studies had addressed the breakdown of VE-cadherin during EndMT led to altered vascular permeability and remolding, which were associated with many disease processes including angiogenesis, ischemia-reperfusion injury, inflammation, and cancer growth and metastasis [36, 37]

Summary

Introduction

Researches indicated the process of Endothelial-Mesenchymal-Transition (EndMT) of vascular endothelial cells (ECs) was critically involved in the progression of tumor. There was still unclear whether the acidic microenvironment affected the EndMT of vascular ECs. Pancreatic cancers often appear metastases in the early phase of the disease, the malignant progression of pancreatic cancer resulting in a poor prognosis for patients with a 5-year survival rate of

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