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  • br Exosomes are membrane enclosed small vesicles nm with end

    2021-03-03


    Exosomes are membrane-enclosed small vesicles (30–100 nm) with endosomal origin that contain numerous molecular components including proteins, mRNAs, as well as miRNAs.35 Exosomes secreted by PSB 1115 play a crucial role in correlating cells and transmit-ting information among tissues over long distances.36 BMSCs have been demonstrated to interact with tumor cells and participate in the progression of multiple tumors, including the processes of cell migration, invasion, and proliferation.37 More specifically, miR-31a-5p transferred by BMSC-derived exosomes has been shown to influence osteogenesis and osteoclastic differentiation.38 During the current study, a key observation was made indicating that BMSC-derived exosomes enriched miR-126-3p. Additionally, miR-126 enriched in exosomes from normal endothelial cells has been reported to contribute to suppressing cell growth and reducing the malignancy of non-small cell lung cancer cells.39 Studies have suggested that exosomes derived from BMSCs could alleviate liver injury of autoimmune hepatitis, which is correlated to the negative regulation of exosomal miR-233 on nucleotide-binding 
    domain and leucine-rich repeat containing protein (NLR) pyrin domain containing 3.40
    The abnormal expression of miRNAs has been widely associated with various human tumors and can be delivered to immune cells by exosomes secreted by tumors.41 Our results provided evidence demonstrating that miR-126-3p transferred by BMSC-derived exo-somes could act to inhibit proliferation, migration, and invasion while promoting the apoptosis of pancreatic cancer cells via the downregu-lation of ADAM9. Hamada et al.24 asserted that upregulation of miR-126 in connection with the knockdown of ADAM9 leads to a reduction in cellular metastasis and invasion in pancreatic cancer, highlighting the crucial role of the miR-126/ADAM9 axis in inhibit-ing the invasive growth of pancreatic cancer cell lines. Moreover, silencing of ADAM9 has been shown to suppress proliferation and induce cell-cycle arrest in G1/G0 phase in prostate cancer cells.33 In our study, proliferation-related factors (Ki67 and VEGF) and inva-sion-related factors (COX-2 and MMP-14) were decreased with the overexpression of miR-126-3p. Ki67, a nuclear protein, could poten-tially serve as a marker during the processes of cell proliferation and cell growth, whereas VEGF has been highlighted as an important regulator in tumor angiogenesis.42 COX-2 and MMPs have been re-ported to influence inflammatory angiogenesis.43 In accordance with our study, studies have reported that miR-126 could target VEGF-A, whereas the expression of miR-126 has been shown to
    have a negative relationship with VEGF-A activity, as well as the expression of MMP-14 in cases of lung cancer.44,45
    In conclusion, the key findings of the present study present evidence indicating that miR-126-3p transferred by BMSCs secreted exosomes acts to suppress proliferation, migration, and invasion, while elevating the rate of apoptosis in pancreatic cancer cells by
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    A
    Proliferation 40
    Figure 9. BMSC-Derived Exosomes Transferred miR-126-3p to Pancreatic Cancer Cells to Influence Their Biological Functions
    (A) Proliferation ability of PANC-1 after transfection de-
    tected by EdU assay (original magnification 400). (B)
    Apoptosis rate of PANC-1 after transfection determined by
    transfection detected by Transwell assay (original magnifi-
    B
    Apoptosis 20
    transfection detected by Transwell assay (original magnifi-
    cation 200). (E) The expression of cell proliferation factor
    determined by western blot analysis. (F) Statistical analysis
    of western blot analysis. The data were measured by the
    mean ± SD, and the data between two groups were
    compared with the independent sample t test for statistical
    and the experiment was repeated three times. BMSC,
    Annexin V-FITC Annexin V-FITC
    of migration 100
    Numbel
    cells 80
    ofinvasive
    Number 20
    human bone mesenchymal stem cell; COX-2, cyclo- oxygenase-2; EdU, 5-ethynyl-20 -deoxyuridine; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; miR-126- 3p, microRNA-126-3p; NC, negative control; VEGF, vascular endothelial growth factor.
    ence, College of PSB 1115 Health Sciences, Jiangsu Normal University. Written informed consents were ob-tained from all patients or guardians prior to their participation. All animal experiments were performed in strict adherence with the principle of using the smallest number of animals in order to complete the experiments. Extensive efforts were made to ensure the pain experienced by the animals during the experiments was minimal.