Abstract
Vasculogenic mimicry (VM) is a kind of tumor vasculature providing blood supply for tumor growth, and the formation of VM is independent of vascular endothelial cells. Instead, VM structures are formed by differentiated tumor cells such as nasopharyngeal carcinoma cells. Recently, studies have shown that anti-angiogenic therapy failed to improve the overall survival for patients, namely, nasopharyngeal carcinoma patients. The existence of VM structure is probably one of the reasons for resistance for anti-angiogenic therapy. Therefore, it is important to study the mechanism for VM formation in nasopharyngeal carcinoma. In this study, the bioinformatic analysis revealed that microRNA-125a-3p (miR-125a) was highly expressed in normal nasopharyngeal epithelial tissue than in nasopharyngeal carcinoma. An in vitro study demonstrated that miR-125a plays an inhibitory role in nasopharyngeal carcinoma cell migration and VM formation, and further studies confirmed that TAZ is a direct downstream target for miR-125a. On this basis, we artificially engineered human mesenchymal stem cells (MSCs) to generate exosomes with high miR-125a expression. Treatment with these miR-125a-over-expressing exosomes attenuated the migration and VM formation in nasopharyngeal carcinoma cells. In addition, the inhibitory role of these exosomes on VM formation and migration in nasopharyngeal carcinoma was also confirmed in vivo. Overall, the current study shows that MSCs can be utilized to generate exosomes with high miR-125a level, which could be therapeutic nanoparticles targeting VM formation in nasopharyngeal carcinoma and used as a complement to anti-angiogenic therapy in the future.
Highlights
Nasopharyngeal carcinoma (NPC) is a unique class of head and neck malignant tumor, and is endemic in eastern parts of Asia and North Africa [1, 2]
To identify miRNA candidates involved in NPC initiation and progression, we analyzed and compared microRNA expression levels between NPC tissue and normal nasopharynx tissue using the Gene Expression Omnibus (GEO) database (NCBI/GEO/ GSE32960)
Heatmap [23] (Figures 1A, B) and volcano plot (Figure 1C) visualization of gene expression were constructed, and we found that miR-125a significantly decreased in NPC tissue samples compared to normal nasopharynx samples
Summary
Nasopharyngeal carcinoma (NPC) is a unique class of head and neck malignant tumor, and is endemic in eastern parts of Asia and North Africa [1, 2]. Recent improvement in treatment has been achieved, many NPC patients still have poor prognosis, suffering distant metastases or locoregional recurrence [3], which is one of the predominant reasons for therapy failure. Studies have focused on the angiogenesis involving endothelial cells activation and recruitment of new vessels in tumor. Clinical trials in head and neck squamous cell carcinoma (HNSCC) show that antiangiogenic drugs such as bevacizumab, have not showed apparent improvement in efficacy [5]. In some cases the anti-angiogenic therapy is discontinued due to poor response to treatment and lifethreatening side effects [6]. The reason may be that the blood supply in a tumor is partially dependent on non-endothelial cell vessels
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