Show simple item record

dc.contributor.authorKanlikilicer, Pinar
dc.contributor.authorBayraktar, Recep
dc.contributor.authorDenizli, Merve
dc.contributor.authorRashed, Mohammed H.
dc.contributor.authorIvan, Cristina
dc.contributor.authorAslan, Burcu
dc.contributor.authorMitra, Rahul
dc.contributor.authorKaragoz, Kubra
dc.contributor.authorBayraktar, Emine
dc.contributor.authorZhang, Xinna
dc.contributor.authorRodriguez-Aguayo, Cristian
dc.contributor.authorEl-Arabey, Amr Ahmed
dc.contributor.authorKahraman, Nermin
dc.contributor.authorBaydogan, Seyda
dc.contributor.authorOzkayar, Ozgur
dc.contributor.authorGatza, Michael L.
dc.contributor.authorOzpolat, Bulent
dc.contributor.authorCalin, George A.
dc.contributor.authorSood, Anil K.
dc.contributor.authorLopez-Berestein, Gabriel
dc.date.accessioned2019-12-12T06:41:11Z
dc.date.available2019-12-12T06:41:11Z
dc.date.issued2018
dc.identifier.issn2352-3964
dc.identifier.urihttps://doi.org/10.1016/j.ebiom.2018.11.004
dc.identifier.urihttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306310/
dc.identifier.urihttp://hdl.handle.net/11655/16647
dc.description.abstractBackground Circulating miRNAs are known to play important roles in intercellular communication. However, the effects of exosomal miRNAs on cells are not fully understood. Methods To investigate the role of exosomal miR-1246 in ovarian cancer (OC) microenvironment, we performed RPPA as well as many other in vitro functional assays in ovarian cancer cells (sensitive; HeyA8, Skov3ip1, A2780 and chemoresistant; HeyA8-MDR, Skov3-TR, A2780-CP20). Therapeutic effect of miR-1246 inhibitor treatment was tested in OC animal model. We showed the effect of OC exosomal miR-1246 uptake on macrophages by co-culture experiments. Findings Substantial expression of oncogenic miR-1246 OC exosomes was found. We showed that Cav1 gene, which is the direct target of miR-1246, is involved in the process of exosomal transfer. A significantly worse overall prognosis were found for OC patients with high miR-1246 and low Cav1 expression based on TCGA data. miR-1246 expression were significantly higher in paclitaxel-resistant OC exosomes than in their sensitive counterparts. Overexpression of Cav1 and anti-miR-1246 treatment significantly sensitized OC cells to paclitaxel. We showed that Cav1 and multi drug resistance (MDR) gene is involved in the process of exosomal transfer. Our proteomic approach also revealed that miR-1246 inhibits Cav1 and acts through PDGFβ receptor at the recipient cells to inhibit cell proliferation. miR-1246 inhibitor treatment in combination with chemotherapy led to reduced tumor burden in vivo. Finally, we demonstrated that when OC cells are co-cultured with macrophages, they are capable of transferring their oncogenic miR-1246 to M2-type macrophages, but not M0-type macrophages. Interpretation Our results suggest that cancer exosomes may contribute to oncogenesis by manipulating neighboring infiltrating immune cells. This study provide a new mechanistic therapeutic approach to overcome chemoresistance and tumor progression through exosomal miR-1246 in OC patients.
dc.relation.isversionof10.1016/j.ebiom.2018.11.004
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleExosomal Mirna Confers Chemo Resistance Via Targeting Cav1/P-Gp/M2-Type Macrophage Axis In Ovarian Cancer
dc.typeinfo:eu-repo/semantics/article
dc.typeinfo:eu-repo/semantics/publishedVersion
dc.relation.journalEBioMedicine
dc.contributor.departmentTıbbi Patoloji
dc.identifier.volume38
dc.identifier.startpage100
dc.identifier.endpage112
dc.description.indexPubMed
dc.description.indexWoS
dc.description.indexScopus


Files in this item

This item appears in the following Collection(s)

Show simple item record