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Exosomal release of microRNA-454 by breast cancer cells sustains biological properties of cancer stem cells via the PRRT2/Wnt axis in ovarian cancer

Aims: Cancer-derived exosomes carrying tumor-derived molecules such as miRNAs and proteins related to various phenotypes have been detected in both the bloodstream and other biofluids of patients with different cancers. Thus, our main purpose here was to determine the role of the exosomal microRNA-454 (miR-454) derived by MDA-MB-231 in self-renewal of cancer stem cells (CSCs) in ovarian cancer (OC).

Materials and methods: Extraction of MDA-MB-231 cells-derived exosomes (231-derived exosomes) was conducted to treat CD44+/CD133+ SKOV3 and CoC1 cells to observe cell growth and stemness. Next, the differentially expressed miRNAs in SKOV3 cells after exosome treatment were filtered using microarray analysis. Subsequently, the cell viability was detected after reducing the exosomal miR-454 and the addition of a Wnt pathway inhibitor C59. Finally, the pro-tumorigenic function of exosomes on OC cells in vivo was investigated.

Key findings: After co-culture with 231-derived exosomes, the stemness of CSCs were promoted. Subsequently, the reduction of exosomal miR-454 weakened the roles of exosomes on cell stemness. Proline-rich transmembrane protein 2 (PRRT2) was substantiated as a target gene of miR-454 in SKOV3 and CoC1 cells. C59 reversed the repressive role of exosomes in stemness of CSCs. When being evaluated in a mouse model, exosomal miR-454 led to an efficacious effect in suppressing the tumor weight and volume in vivo.

Significance: Altogether, 231-derived exosomes carrying miR-454 disrupted the Wnt pathway by targeting PRRT2, thereby promoting CSC stemness in vitro and OC cell growth in vivo.

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S7037 Wnt-C59 (C59) Wnt-C59 (C59) is a PORCN inhibitor for Wnt3A-mediated activation of a multimerized TCF-binding site driving luciferase with IC50 of 74 pM in HEK293 cells.

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Wnt/beta-catenin