Jagged1 contained in MSC-derived small extracellular vesicles promotes squamous differentiation of cervical cancer by activating NOTCH pathway

Abstract

Purpose Cervical cancer is the fourth most common cancer in women and poses a major threat to women's health, urgently requiring new treatment methods. Methods This study first successfully extracted and identified small extracellular vesicles secreted by human umbilical cord-derived mesenchymal stem cells. We studied the effects of MSC-sEV on the squamous differentiation levels of cervical cancer CaSki cells in vitro, and explored the effects of MSC-sEV on the NOTCH pathway, the growth, proliferation, migration abilities and squamous differentiation levels of cervical cancer cells. The roles of MSC-sEV were also verified in human keratinocyte HaCaT cells. Results The results showed that Jagged1 protein on MSC-sEV can bind to NOTCH1 on cervical cancer cells, activate NOTCH signaling, and promote squamous differentiation levels in CaSki cells, thus inhibiting the growth, proliferation and migration abilities of CaSki cells. MSC-sEV can also activate the NOTCH pathway in HaCaT cells, but promote the viability of HaCaT cells. Conclusion MSC-sEV can activate the NOTCH pathway to promote squamous differentiation of CaSki cells and inhibit the growth proliferation and migration abilities of CaSki cells which may be a new mechanism for cervical cancer treatment.

Transforming native exosomes to engineered drug vehicles: A smart solution to modern cancer theranostics

“…Drugs having molecular weight less than 400 Da with maximum of 7 H-bonds can only pass through BBB via lipid-mediated diffusion. [72] Being nano-sized vesicle with high biocompatibility due to recognition of target sites by ) [35,36] Lipid-Anchored Outer Membrane Proteins Cellular prion protein, GPI-anchored proteins, Glypican-1, Ectonucleotidases CD73 and CD39, Complement-inhibiting proteins CD59 and CD55, Sperm receptor Juno, Hedgehog morphogens [37,38] Peripheral Surface Proteins Wingless, Evenness interrupted/ GPR177, transforming growth factor β, Tumor necrosis factor, Fas ligand, Cytokines, Fibronectin, Tenascin C, ECM1, MFGE8/lactadherin [39][40][41] Lipid-Anchored Inner Membrane Proteins Palmitoylated membrane proteins, GTPases (Rho, Rabs, Ras), Myristoylated signaling kinases Src, Activity-regulated cytoskeletal/ARC protein, Acylated Gag proteins, [42,43] Inner Peripheral Membrane Proteins EBP50, ERM, CD43, CD44, IgSF8, ALIX, PTGFRN, Syntenin, Hsp20, Hsp27, Hsp40/DnaJ proteins, Hsp70, Hsp90, and α/β-crystallins [44][45][46] Enzymes CD73, CD39, Calcium-binding anexins, Phosphatases, Pyrophosphatases, and Phosphate transporters, RNA editing enzymes, Proteases, Glycosyltransferases, Lipases, Glycosidases, and metabolic enzymes, Hyaluronan synthase-3, Glycolytic enzymes [47,48] Cytoskeletal proteins Actin, Profilin I, Elongation factor-1a, Fibronectin cofilin, Tubulin [49] Lipids Golgi-derived lipids Cholesterol, Phospholipids, Phosphatidylethanolamines, Polyglycerols, and Diglycerides, Glycosphingolipids [50] Enzymes Phospholipase C and D and Prostaglandin [51] Metabolites Carboxylic acids, Cyclic alcohols, Biogenic amines, Vitamins, Amino acids, Carnitines, Sugars, Intermediates of TCA cycle Valine, Threonine, Glutamine, Serine and Cystine, Citrate, Pyruvic acid, Malic acid, α-ketoglutaric acid and Fumaric acid [52,53] Abbreviations: ALIX: ALG-2-interacting protein X; ARC: Activity-regulated cytoskeletal protein; EBP: Emopamil binding protein; ECM1: Extracellular matrix Protein 1; EGFR: Epidermal growth factor receptor; ERM: Ezrin-radixin-moesin; GPCR: G-protein coupled receptor; GPI: Glycosylphosphatidylinositol; HSP: Heat shock proteins; ICAN-1: Intercellular Adhesion Molecule-1; IgSF: Immunoglobin superfamily; MFGE8: Milk fat globule epidermal growth factor 8; MHC: Major histocompatibility complex; PD-L1: Programmed death-ligand-1; PTGFRN: Prostaglandin F2 receptor negative regulator; SDC: Sex determination and dosage compensation; TCA: Tri-carboxylic acid; VEGFR: Vascular endothelial growth factor receptor.…”