Extracellular Vesicle-Encapsulated MicroRNA-375 from Bone Marrow-Derived Mesenchymal Stem Cells Inhibits Hepatocellular Carcinoma Progression through Regulating HOXB3-Mediated Wnt/β-Catenin Pathway.

Zhaoxia Yu,Qiqi Fan,Xiaobin Wang,Ju Liu,Xiaoting Ren,Jun Yu,Elena Andreucci

doi:10.1155/2022/9302496

Abstract

Nowadays, microRNA-375 (miR-375) has been implicated in many types of cancers, including hepatocellular carcinoma (HCC), and the functions of miRNAs encapsulated by extracellular vesicles (EV) in HCC progression have also been extensively investigated. In this research, we aimed to probe into the mechanism of EV-encapsulated miR-375 from bone marrow-derived mesenchymal stem cells (BM-MSCs) in HCC progression. At first, miR-375 expression in HCC tissues and cells was detected using RT-qPCR, and miR-375 was overexpressed to specify the effects of miR-375 on the malignant phenotype of HCC cells. miR-375 was downregulated in HCC, and overexpression of miR-375 suppressed HCC cell growth. Then, BM-MSCs and EV were isolated and identified, and, EV were cocultured with HCC cells for further functional assays. It was found that miR-375 encapsulated by EV could restrict the malignant phenotypes of HCC cells. Furthermore, the downstream genes and signaling cascades involved in HCC growth were investigated. HOXB3 was determined to be a downstream target of miR-375, and upregulation of miR-375 decreased Wnt1 and β-catenin protein expression. Furthermore, HOXB3 blocked the repressive effects of miR-375 on HCC cells and Wnt1 and β-catenin expression. This study highlights that miR-375 encapsulated by EV inhibits HCC development via modulating the HOXB3/Wnt/β-catenin axis.

Highlights

Hepatocellular carcinoma (HCC) is a common type of cancer with poor prognosis, and this disease is a major healthy burden around the world [1, 2]
We further analyzed the correlation between miR-375 expression and survival of patients in The Cancer Genome Atlas- (TCGA-) liver hepatocellular carcinoma (LIHC) by Kaplan-Meier analysis, and we found that LIHC patients with high miR-375 expression had higher survival rate (Figure 1(b))
HCC cell malignant phenotypes were determined by EdU assay, flow cytometry, and Transwell assay, and the results revealed that relative to the extracellular vesicles (EV)-negative control (NC) mimic+oe-NC treatment, the EV-miR-375 mimic+oe-NC treatment reduced proliferation rate, increased apoptosis rate, and decreased number of migratory and invasive cells in HCC cells

Summary

Introduction

Hepatocellular carcinoma (HCC) is a common type of cancer with poor prognosis, and this disease is a major healthy burden around the world [1, 2]. The potential treatment regimens consist of resection, local ablative therapies, and liver transplantation, while these therapies are not applicable for patients at advanced stages [5] who exhibit therapeutic resistance and low response rate [6]. To ease these situations, effective biomarkers are needed for HCC in terms of early detection and prognosis. Extracellular vesicles (EVs) represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and RNA [10].

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