Dataset Information

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 PDGF? 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.

SUBMITTER: Kanlikilicer P

PROVIDER: S-EPMC6306310 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer.

Kanlikilicer Pinar P Bayraktar Recep R Denizli Merve M Rashed Mohammed H MH Ivan Cristina C Aslan Burcu B Mitra Rahul R Karagoz Kubra K Bayraktar Emine E Zhang Xinna X Rodriguez-Aguayo Cristian C El-Arabey Amr Ahmed AA Kahraman Nermin N Baydogan Seyda S Ozkayar Ozgur O Gatza Michael L ML Ozpolat Bulent B Calin George A GA Sood Anil K AK Lopez-Berestein Gabriel G

EBioMedicine 20181125

<h4>Background</h4>Circulating miRNAs are known to play important roles in intercellular communication. However, the effects of exosomal miRNAs on cells are not fully understood.<h4>Methods</h4>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 ...[more]

PMID: 30487062

Similar Datasets

Project description:Background: Exosomes are extracellular microvesicles that are released by most cells and widely distributed in various body fluids. Malignant cells secrete large amounts of exosomes containing various molecular constituents reflecting the originating tumor. We investigated the difference in microRNA (miRNA) expression in serum exosomes from the patients with benign, borderline and malignant ovarian masses to assess the diagnostic relevance of serum exosomal miRNAs as biomarkers for preoperative diagnosis of ovarian carcinoma. Methods: A total of 68 cases of ovarian masses were enrolled, comprising benign ovarian cysts (benign; n=10), borderline ovarian tumors (BOT, n=10), high-grade serous ovarian carcinomas (HGSOC, n=39) and non-HGSOCs (n=9). Exosomal RNA was extracted from the serum, and expression levels of seven miRNAs (miRNA-21, -93, -141, -145, -200a, -200b and -200c), which were reportedly dysregulated in serous ovarian cancer in previous studies, were quantified by real-time PCR, and compared between the four groups. Results: MiR-93, -145, and -200c, showed significantly higher expression in serum exosomes of the cancer group (HGSOC and non-HGSOC) than of the non-cancer group (benign and BOT; all p<0.05). The remaining three miRs (miR-141, -200a, and -200b) were expressed at extremely low levels, and not appropriate as serological biomarkers. To test discrimination of cancer from non-cancer, the area under the receiver operating characteristic curves determined for cancer antigen 125 (CA125), miR-145, miR-200c, miR-21, and miR-93 were 0.801 (p<0.001), 0.910 (p<0.001), 0.802 (p<0.001), 0.585 (p=0.303), and 0.755 (p=0.002), respectively. MiR-145 showed superior sensitivity (91.6%), and miR-200c showed superior specificity (90.0%), compared with CA125. Conclusion: Expression of exosomal miR-93, miR-145 and miR-200c was significantly elevated in the serum of ovarian cancer patients. Serum exosomal miR-145 in particular appeared to be the most promising biomarker for preoperative diagnosis of ovarian cancer.

Dataset Information

Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer.

Background

Methods

Findings

Interpretation

Publications

Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer.

Similar Datasets

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