@article{582a3fe43b8d432ba3f2a36ae8bef3e7,
title = "Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer",
abstract = "Background: 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.",
keywords = "Cav1, Exosome, Ovarian cancer, P-gp, miR-1246, oncomiR",
author = "Pinar Kanlikilicer and Recep Bayraktar and Merve Denizli and Rashed, {Mohammed H.} and Cristina Ivan and Burcu Aslan and Rahul Mitra and Kubra Karagoz and Emine Bayraktar and Xinna Zhang and Cristian Rodriguez-Aguayo and El-Arabey, {Amr Ahmed} and Nermin Kahraman and Seyda Baydogan and Ozgur Ozkayar and Gatza, {Michael L.} and Bulent Ozpolat and Calin, {George A.} and Sood, {Anil K.} and Gabriel Lopez-Berestein",
note = "Funding Information: This publication is part of the NIH Extracellular RNA Communication Consortium paper package and was supported by the NIH Common Fund{\textquoteright}s exRNA Communication Program. This study was funded by the NIH Common Fund ( UH3 TR000943 ), through the Office of Strategic Coordination/Office of the NIH Director and MD Anderson's Cancer Center Support Grant (CCSG) ( CA016672 ) to G. Lopez-Berestein, A.K. Sood, G.A. Calin, the American Cancer Society Research Professor Award to A.K. Sood, and The Center for RNA Interference and Non-Coding RNA to G.A. Calin, A.K. Sood, and G. Lopez-Berestein and CA166228 from the National Cancer Institute of the NIH to MLG. DHFS-18PPC-024 from the New Jersey Commission for Cancer Research to KK. Dr. Calin is the Felix L. Haas Endowed Professor in Basic Science. Work in Dr. Calin's laboratory is supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC), the NCI grants 1R01 CA182905-01 and 1R01CA222007-01A1 , an NIGMS 1R01GM122775-01 grant, a U54 grant #CA096297/CA096300 – UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project, a Team DOD ( CA160445P1 ) grant, a Sister Institution Network Fund (SINF) 2017 grant, and the Estate of C. G. Johnson, Jr. Funding Information: This publication is part of the NIH Extracellular RNA Communication Consortium paper package and was supported by the NIH Common Fund's exRNA Communication Program. This study was funded by the NIH Common Fund (UH3 TR000943), through the Office of Strategic Coordination/Office of the NIH Director and MD Anderson's Cancer Center Support Grant (CCSG) (CA016672) to G. Lopez-Berestein, A.K. Sood, G.A. Calin, the American Cancer Society Research Professor Award to A.K. Sood, and The Center for RNA Interference and Non-Coding RNA to G.A. Calin, A.K. Sood, and G. Lopez-Berestein and CA166228 from the National Cancer Institute of the NIH to MLG. DHFS-18PPC-024 from the New Jersey Commission for Cancer Research to KK. Dr. Calin is the Felix L. Haas Endowed Professor in Basic Science. Work in Dr. Calin's laboratory is supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC), the NCI grants 1R01 CA182905-01 and 1R01CA222007-01A1, an NIGMS 1R01GM122775-01 grant, a U54 grant #CA096297/CA096300 ? UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project, a Team DOD (CA160445P1) grant, a Sister Institution Network Fund (SINF) 2017 grant, and the Estate of C. G. Johnson, Jr. Funding Information: This publication is part of the NIH Extracellular RNA Communication Consortium paper package and was supported by the NIH Common Fund's exRNA Communication Program. This study was funded by the NIH Common Fund (UH3 TR000943), through the Office of Strategic Coordination/Office of the NIH Director and MD Anderson's Cancer Center Support Grant (CCSG) (CA016672) to G. Lopez-Berestein, A.K. Sood, G.A. Calin, the American Cancer Society Research Professor Award to A.K. Sood, and The Center for RNA Interference and Non-Coding RNA to G.A. Calin, A.K. Sood, and G. Lopez-Berestein and CA166228 from the National Cancer Institute of the NIH to MLG. DHFS-18PPC-024 from the New Jersey Commission for Cancer Research to KK. Dr. Calin is the Felix L. Haas Endowed Professor in Basic Science. Work in Dr. Calin's laboratory is supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC), the NCI grants 1R01 CA182905-01 and 1R01CA222007-01A1, an NIGMS 1R01GM122775-01 grant, a U54 grant #CA096297/CA096300 – UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project, a Team DOD (CA160445P1) grant, a Sister Institution Network Fund (SINF) 2017 grant, and the Estate of C. G. Johnson, Jr. Publisher Copyright: {\textcopyright} 2018",
year = "2018",
month = dec,
doi = "10.1016/j.ebiom.2018.11.004",
language = "English (US)",
volume = "38",
pages = "100--112",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}