Exosomal Delivery of AntagomiRs Targeting Viral and Cellular MicroRNAs Synergistically Inhibits Cancer Angiogenesis

Abstract

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated cancer characterized by a high degree of recurrence, angiogenesis, and metastasis. The importance of alternative pro-angiogenesis pathways including viral factors has emerged after decades of directly targeting various signaling components. Using NPC as a model, we identified an essential oncogenic pathway underlying angiogenesis regulation that involves the inhibition of a tumor suppressor, Spry3, and its downstream targets by EBV-miR-BART10-5p (BART10-5p) and hsa-miR-18a (miR-18a). Overexpression of EBV-miR-BART10-5p and hsa-miR-18a strongly promotes angiogenesis in vitro and in vivo by regulating the expression of VEGF and HIF1-α in a Spry3-dependent manner. In vitro or in vivo treatment with iRGD-tagged exosomes containing antagomiR-BART10-5p and antagomiR-18a preferentially suppressed the angiogenesis and growth of NPC. Our findings first highlight the role of EBV-miR-BART10-5p and oncogenic hsa-miR-18a in NPC angiogenesis and also shed new insights into the clinical intervention and therapeutic strategies for nasopharyngeal carcinoma and other virus-associated tumors.

Exosomal LBH inhibits epithelial-mesenchymal transition and angiogenesis in nasopharyngeal carcinoma via downregulating VEGFA signaling

“…For exosome-mediated paracrine signaling, NPC-derived exosomes have been reported to either enhance or suppress angiogenesis upon uptake by HUVECs due to exosomal delivery of functional biomolecules [48][49][50]. Our Matrigel plug assay indicated that treatment with LBH+ exosomes decelerated in vivo angiogenesis.…”

Analysis of Prognostic Factors of Nasopharyngeal Carcinoma and Construction of Risk Nomogram Prediction Model

“…Huang and colleagues [17] using the clinicopathological data of 1286 NPC patients found that the degree of differentiation of NPC tumor cells was closely related to their biological behavior, and affected tumor staging, lymph node metastasis and treatment, which consequently led to various prognosis in NPC patients. In addition, other domestic and international studies found that the degree of differentiation of nasopharyngeal carcinoma tumor cells was closely related to the degree of malignancy, and affected the survival and prognosis of patients [18][19][20]. The higher the differentiation of nasopharyngeal carcinoma tumor cells had the better the prognosis of patients..…”

The role of Exosomes in the Pathogenesis of Nasopharyngeal Carcinoma and the involved Clinical Application

“…EBV-related products in the exosomes of NPC can also affect tumor progression, such as the EBV-encoding RNAs (EBERs). For instance, EBERs regulate the expression of vascular cell adhesion molecule 1 (VCAM-1) through TLR3/RIG-I to induce angiogenesis 47 ; EBV-miR-BART10-5p and miR-18a strongly promote angiogenesis and tumor growth of NPC by mediating the expression of VEGF and HIF1-α in a Spry3-dependent manner 48 . More important, the exosomal molecules not only have the ability to accelerate angiogenesis but also hold inhibitory functions.…”

“…In NPC, a number of key regulatory molecules involved in the tumor pathological process have been identified and a few of them have been used for novel cancer immunotherapy in vitro or in vivo . A research team has worked to incorporate antagomiR targeting BART10-5p and miR-18a (which are intended to promote angiogenesis) into iRGD-tagged exosomes, resulting in preferentially suppressed angiogenesis and growth of NPC 48 . Delivering miR-34c (a tumor suppressor of NPC) to the cancerous cells through mesenchymal stem cell exosomes can impede β-chain protein and slow down the invasion, metastasis, proliferation and EMT of NPC cells, ultimately inhibiting tumor deterioration and radiation resistance 5 .…”