Abstract
Hypoxia-exposed lung cancer-released exosomal microRNA-23a (miR-23a) has been shown to enhance angiogenesis as well as vascular permeability, contributing to the close correlation between exosomal miR-23a and tumorigenesis. The current study aimed to investigate whether gastric cancer (GC) cell-derived exosomal miR-23a could induce angiogenesis and to elucidate the potential mechanisms associated with the process. Differentially expressed miRNAs in GC were initially screened from the Gene Expression Omnibus database. Target genes were selected following miRNA-mRNA prediction and subsequently verified by dual luciferase reporter assay. RT-qPCR was conducted to detect miR-23a and PTEN expression in GC tissues, cells and exosomes. Human umbilical venous endothelial cells (HUVECs) were co-cultured with GC cell-derived exosomes to assess the angiogenesis mediated by exosomes in vitro. Additionally, PTEN was overexpressed in HUVECs to analyze the mechanism by which miR-23a regulates angiogenesis. miR-23a was highly expressed in GC tissues and cells and GC cell-derived exosomes. Angiogenesis was promoted by the co-culture of HUVECs and GC cells-derived exosomes, as evidenced by the increased expression of VEGF but decreased expression of TSP-1. PTEN was targeted by miR-23a and was lowly expressed in GC tissues. In a co-culture system, miR-23a carried by GC cells-derived exosomes promoted angiogenesis via the repression of PTEN. Collectively, GC cell-derived exosomal miR-23a could promote angiogenesis and provide blood supply for growth of GC cells. This study contributes to advancement of miRNA-targeted therapeutics.
Highlights
Gastric cancer (GC) is a heterogeneous malignancy with epidemiologic and histopathologic differences around the world [1]
Based on the GSE78091 dataset retrieved from the Gene Expression Omnibus (GEO) database and data from the Cancer Genome Atlas (TCGA), we detected that miR-23a was robustly induced in gastric cancer (GC) (Figures 1B,C)
Western blot analysis exhibited that compared with adjacent normal tissues, the protein expression of vascular endothelial growth factor (VEGF) was notably increased, but that of TSP-1 was diminished in GC tissues (Figure 1F), indicating that tube formation was more prominent in GC tissues
Summary
Gastric cancer (GC) is a heterogeneous malignancy with epidemiologic and histopathologic differences around the world [1]. Exosomes have emerged as effective drug and gene therapeutic transporters for a wide variety of pathologies [4]. Exosomes are Exosomal miR-23a in Gastric Cancer cell-derived vesicles with diameter ranging from 20 to 100 nm, capable of influencing angiogenesis, metastasis and other biological cellular properties related to tumorigenesis [5]. EGFR delivered by exosomes has been reported to contribute to the liver microenvironment to accelerate liver-specific metastasis of GC [6]. Cancer cell-derived exosomes facilitate GC progression by transferring foreign microRNAs (miRNAs), which has shed new light on the mechanism of tumorigenesis and potential novel targets for GC treatment [7]. Genetic and epigenetic abnormalities such as changes in miRNA and gene profiles have been widely implicated in gastric carcinogenesis [8, 9]
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