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MiR-144 delivered by nasopharyngeal carcinoma-derived EVs stimulates angiogenesis through the FBXW7/HIF-1α/VEGF-A axis.

ABSTRACT: The current study aimed to explore the role of tumor-derived extracellular vesicles (EVs) in angiogenesis during nasopharyngeal carcinoma (NPC). NPC biopsy specimens were initially collected. Human umbilical vein endothelial cells (HUVECs) were co-cultured with EVs isolated from NPC cells, after which their migration, invasion, as well as vessel-like tube formation were evaluated by Transwell chamber systems and Matrigel-based angiogenesis assays. The pro-angiogenic activities of EVs as well as the candidate microRNA (miRNA or miR) were examined using an in vivo Matrigel angiogenesis model. The results indicated that the levels of miR-144 in the NPC tissues were upregulated when compared to the nasopharyngeal normal tissues in addition to the identification of a positive correlation with the expression of CD31. Moreover, our data indicated that miR-144 was highly enriched in EVs from NPC cells and then ultimately enhanced the migration and invasion of HUVECs and vessel-like tubes in vitro and in vivo. Notably, miR-144 was identified as a mediator in NPC-EV-induced regulatory effects through the inhibition of the target gene FBXW7 and promotion of the transcriptional factor HIF-1α-dependent vascular endothelial growth factor (VEGF-A). Taken together, the key findings of the current study highlighted the role of miR-144 as an extracellular pro-angiogenic mediator in NPC tumorigenesis.

SUBMITTER: Tian X

PROVIDER: S-EPMC8143977 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAldehyde dehydrogenase 1A1 (ALDH1A1), a member of aldehyde dehydrogenase family, is a marker of stemness in breast cancer. During tumor progression cancer stem cells (CSCs) have been reported to secrete angiogenic factors to orchestrate the formation of pathological angiogenesis. This vasculature can represent the source of self-renewal of CSCs and the route for further tumor spreading. The aim of the present study has been to assess whether ALDH1A1 controls the output of angiogenic factors in breast cancer cells and regulates tumor angiogenesis in a panel of in vitro and in vivo models.MethodsStemness status of breast cancer cells was evaluated by the ability to form turmorspheres in vitro. A transwell system was used to assess the angiogenic features of human umbilical vein endothelial cells (HUVEC) when co-cultured with breast cancer cells MCF-7 harboring different levels of ALDH1A1. Under these conditions, we survey endothelial proliferation, migration, tube formation and permeability. Moreover, in vivo, MCF-7 xenografts in immunodeficient mice allow to evaluate blood flow, expression of angiogenic factors and microvascular density (MVD).ResultsIn MCF-7 we observed that ALDH1A1 activity conferred stemness property and its expression correlated with an activation of angiogenic factors. In particular we observed a significant upregulation of hypoxia inducible factor-1α (HIF-1α) and proangiogenic factors, such as vascular endothelial growth factor (VEGF). High levels of ALDH1A1, through the retinoic acid pathway, were significantly associated with VEGF-mediated angiogenesis in vitro. Co-culture of HUVEC with ALDH1A1 expressing tumor cells promoted endothelial proliferation, migration, tube formation and permeability. Conversely, downregulation of ALDH1A1 in MCF-7 resulted in reduction of proangiogenic factor release/expression and impaired HUVEC angiogenic functions. In vivo, when subcutaneously implanted in immunodeficient mice, ALDH1A1 overexpressing breast tumor cells displayed a higher expression of VEGF and MVD.ConclusionIn breast tumors, ALDH1A1 expression primes a permissive microenvironment by promoting tumor angiogenesis via retinoic acid dependent mechanism. In conclusion, ALDH1A1 might be associated to progression and diffusion of breast cancer.

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MiR-144 delivered by nasopharyngeal carcinoma-derived EVs stimulates angiogenesis through the FBXW7/HIF-1α/VEGF-A axis.

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