Extracellular Vesicles Containing MicroRNA-92a-3p Facilitate Partial Endothelial-Mesenchymal Transition and Angiogenesis in Endothelial Cells

Abstract

Extracellular vesicles (EVs) are nanometer-sized membranous vesicles used for primitive cell-to-cell communication. We previously reported that colon cancer-derived EVs contain abundant miR-92a-3p and have a pro-angiogenic function. We previously identified Dickkopf-3 (Dkk-3) as a direct target of miR-92a-3p; however, the pro-angiogenic function of miR-92a-3p cannot only be attributed to downregulation of Dkk-3. Therefore, the complete molecular mechanism by which miR-92a-3p exerts pro-angiogenic effects is still unclear. Here, we comprehensively analyzed the gene sets affected by ectopic expression of miR-92a-3p in endothelial cells to elucidate processes underlying EV-induced angiogenesis. We found that the ectopic expression of miR-92a-3p upregulated cell cycle- and mitosis-related gene expression and downregulated adhesion-related gene expression in endothelial cells. We also identified a novel target gene of miR-92a-3p, claudin-11. Claudin-11 belongs to the claudin gene family, which encodes essential components expressed at tight junctions (TJs). Disruption of TJs with a concomitant loss of claudin expression is a significant event in the process of epithelial-to-mesenchymal transition. Our findings have unveiled a new EV-mediated mechanism for tumor angiogenesis through the induction of partial endothelial-to-mesenchymal transition in endothelial cells.

Endothelial-to-Mesenchymal Transition in Cancer

“…Patients biopsies, cellular model (Fan et al, 2018) EVs (mir-92a) Angiogenesis Cellular model (Yamada et al, 2019) Pancreatic cancer nd Source of CAFs Patient biopsies, murine model (Zeisberg et al, 2007;Fan et al, 2019) Endoglin deficiency Metastasis Murine model (Anderberg et al, 2013) Lung cancer Radiation Resistance to radiotherapy Patients biopsies, murine model (Choi et al, 2018) Tumor secretome Resistance to chemotherapy Cellular model (Kim et al, 2019) Glioblastoma HGF/β-catenin Resistance to chemotherapy Patients biopsies, murine model (Huang et al, 2016(Huang et al, , 2020 PDGF Resistance to anti-angiogenic agents Murine model (Liu T. et al, 2018) Oral squamous carcinoma Wnt-5b Lymphangiogenesis Cellular model (Wang et al, 2017) Esophageal cancer TGF-β2-IL1β Source of CAFs Patients biopsies, cellular model (Nie et al, 2014) OPN, osteopontin; EV, extracellular vesicles; CAFs, cancer-associated fibroblasts; TGF-β, transforming growth factor-β; PDGF, platelet derived growth factor; nd, not determined. Toullec et al, 2018).…”

“…Moreover, the master EndMT transcription factors Slug and Snail are found expressed in tumor ECs in several carcinoma (Welch-Reardon et al, 2015), with Slug expression recently associated with angiogenesis and tumor metastasis (Gu et al, 2017). Recently, colon cancer cells, via extracellular vesicles, have been shown to induce a partial EndMT associated with angiogenesis, in a miR-92a-dependent inhibition of junctional Claudin-11 and up-regulation of Snail, and vimentin (Yamada et al, 2019). Partial EndMT, stimulated by tumor-secreted Wnt ligand, has also been involved in oral cancer lymphangiogenesis (Wang et al, 2017).…”

Role of Non-Coding RNAs in the Development of Targeted Therapy and Immunotherapy Approaches for Chronic Lymphocytic Leukemia

“…Indeed, while studying the ability of leukemia cells to communicate with endothelial cells, Umezu et al discovered that miR-92a-3p is selectively transferred from donor cells to endothelial cells via EVs [72]. More recently, a study on colon cancer showed that EVs containing miR-92a-3p can facilitate the endothelial-mesenchymal transition and the angiogenesis process affecting the TME [226]. As mentioned in Section 2, the same molecule is involved in a mechanism of activation of the VEGF-based autocrine pathway in CLL B-cells which leads to disease progression and is associated with poor prognosis in CLL [50,51,227].…”

Angioregulatory microRNAs in Colorectal Cancer

“…MiR-92a DKK3 and claudin-11 [36] MiR-1246 PML inhibition and SMAD 1/5/8 signaling activation [37] MiR-1229 HIPK2 [38] MiR-25-3p KLF2 and KLF4 [39] MiR-181a-5p SRC/VEGF signaling [40] MiR-194 THBS1 [41] MiR-130b PPARγ [42] MiR-27a SMAD4 [43] Antiangiogenic MiRNAs…”

“…A miR-92a/KLF4/p21 axis facilitates CRC cell proliferation and migration [102]. Exosome-mediated transfer of miR-92a from colon cancer cells to endothelial cells leads to angiogenesis induction through downregulation of Dickkopf-3 (DKK3) and claudin-11 [36]. Several studies have shown that DKK3 has a diverse function in tumor angiogenesis and oncogenesis [103][104][105][106].…”