Hypoxia-Induced miR-210 Promotes Endothelial Cell Permeability and Angiogenesis via Exosomes in Pancreatic Ductal Adenocarcinoma

Abstract

Background. Exosomes have been proven to play important diagnostic, regulatory, or communication roles in tumorigenesis, tumor progression, or metastasis; in recent studies, lots of molecules, including miRNAs, were found to be aberrantly expressed in tumor exosomes and were correlated with tumor development. However, studies about the expression, relationship, or control mechanisms of miRNAs in exosomes in pancreatic ductal adenocarcinoma (PDAC) are scarce and urgently needed. The aim of this article was to identify and investigate abnormally expressed miRNAs in PDAC exosomes in vivo and in vitro. Methods. Microarray studies were used to detect aberrantly expressed miRNAs in PDAC exosomes, and miR-210 expression in cells or exosomes was further analyzed by qRT-PCR. Bioinformatics analyses, dual-luciferase assays, WB, and other assays were utilized to explore the miRNA molecular mechanisms. The living cell coculture model and immunofluorescence analysis were employed to image the communication between PDAC cells and endothelial cells. Other biological experiments in the study include a real-time intravital imaging system, EdU, transwell, xenograft models, and so on. Results. miR-210 is significantly expressed in PDAC exosomes and malignant cells. High miR-210 significantly facilitated tumor angiogenesis, cell invasion, and proliferation in PDAC cells. Further mechanistic detection revealed that miR-210 negatively regulated EFNA3 expression and participated in the PI3K/AKT/VEGFA or Wnt/Β-catenin/RHOA pathways, thus promoting tumor angiogenesis and cellular permeability. PDAC cells promote endothelial angiogenesis or permeability via miR-210 transmission by tumor exosomes. Exosomal miR-210 promotes PDAC progression in vivo. Further detection of PDAC plasma exosomal miR-210 suggests that exosomal miR-210 expression was high and significantly associated with vascular invasion and TNM stage and was an independent risk factor for PDAC overall survival. Conclusions. PDAC cell-secreted exosomes could promote angiogenesis and cellular permeability of neighboring endothelial angiogenesis or permeability via miR-210 transmission. Exosomal miR-210 may play important roles in tumor biology and may be a useful prognostic marker in PDAC.

Exercise-Induced miR-210 Promotes Cardiomyocyte Proliferation and Survival and Mediates Exercise-Induced Cardiac Protection against Ischemia/Reperfusion Injury

“…Previous studies have reported that EFNA3 is targeted by miR-210 in multiple cell types [ 31 , 32 ]. However, the question of whether miR-210 could regulate EFNA3 in cardiomyocyte proliferation and/or apoptosis remained unanswered.…”

“…However, its role in the myocardium has been relatively underexplored. In addition, we evaluated EFNA3, a previously identified target of miR-210 [ 31 , 32 ], in the myocardium and in the I/R injury model after swimming regimen. Increasing evidence has indicated that EFNA3 participates to regulate apoptosis in different cell types such as nucleus pulposus cells, vascular endothelial cells, Müller cells, and sensory axon [ 59 – 62 ].…”

Impact of Hypoxia-Induced miR-210 on Pancreatic Cancer

“…These findings imply that miR-210's promotion of proliferation and invasion, mediated through EFNA3, holds significance in MPNST tumourigenesis and progression [72]. Another study further elucidated the mechanism in PC, which indicates that miR-210 expression exhibits significant upregulation in both PDAC exosomes and malignant cells [73]. Elevated levels of miR-210 play a pivotal role in enhancing tumour angiogenesis, cell invasion, and proliferation in PDAC cells.…”

Expression of Selected miRNAs in Undifferentiated Carcinoma with Osteoclast-like Giant Cells (UCOGC) of the Pancreas: Comparison with Poorly Differentiated Pancreatic Ductal Adenocarcinoma

“…This participation facilitates tumor angiogenesis and enhances cellular permeability. In vivo studies have corroborated that exosomal miR-210 plays a significant role in driving the progression of pancreatic ductal adenocarcinoma [81,82]. Yu et al analyzed plasma levels of miR-196a and miR-210 with RT-qPCR in a cohort of 31 PDAC patients.…”