Gastric Cancer Cell-Derived Exosomal microRNA-23a Promotes Angiogenesis by Targeting PTEN

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.

The Role and Expression of Angiogenesis-Related miRNAs in Gastric Cancer

“…The same study demonstrated that the upregulation of another miRNA, miR-616-3p, in GC tissues resulted in the downregulation of PTEN and PI3K/AKT/mTOR pathway activation through PTEN, which then contributed to EMT and angiogenesis [ 23 ]. A second study confirmed the relevance of miR-23a, and a third study confirmed the relevance of miR-616-3p in GC [ 60 , 70 ]. In the study by Du et al, miR-23a was highly expressed in GC tissues, cells, and GC cell-derived exosomes.…”

“…In the study by Du et al, miR-23a was highly expressed in GC tissues, cells, and GC cell-derived exosomes. This miRNA was demonstrated to promote angiogenesis via the repression of PTEN in a co-culture system [ 70 ]. The role of miR-616-3p as a promoter of angiogenesis via the PTEN/AKT/mTOR pathway in GC has also been confirmed in the study by Wu et al [ 60 ].…”

The Significance of Exosomal RNAs in the Development, Diagnosis, and Treatment of Gastric Cancer

“…For instance, miR-130a from gastric cancer cells-derived exosomes can enter vascular cells and target C-MYB, a transcription factor of angiogenesis, to promote angiogenesis and tumor growth [ 56 ]. MiR-23a carried by GC cells-derived exosomes can be used by vascular cells and suppress the expression of a well-known tumor suppressor gene, PTEN to promote angiogenesis [ 57 ]. These exosomal RNAs from TDEs can target vascular cells and promote angiogenesis though expression alternation of transcription factor or tumor suppressor gene.…”

The Role of Exosomes in Thyroid Cancer and Their Potential Clinical Application

“…The growth and metastasis of malignant tumors depend on the formation and dilation of blood vessels (95). Exosomes from various tumors, such as breast cancer (15), colorectal cancer (96), gastric cancer (97), and lung cancer (80), have been shown to play an important role in promoting angiogenesis. It should be noted that the exact mechanism of exosome-driven angiogenesis is not clear, and the angiogenic characteristics of exosome cargoes from different tumor cells vary widely (98).…”