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posted on 2023-03-31, 00:31 authored by Pinar Kanlikilicer, Mohammed H. Rashed, Recep Bayraktar, Rahul Mitra, Cristina Ivan, Burcu Aslan, Xinna Zhang, Justyna Filant, Andreia M. Silva, Cristian Rodriguez-Aguayo, Emine Bayraktar, Martin Pichler, Bulent Ozpolat, George A. Calin, Anil K. Sood, Gabriel Lopez-Berestein Supplementary Data includes Supplementary Figures 1-6 and Supplementary Tables 1-3. Supplementary Figure 1 shows microscopic images for the characterization of exosomes. Supplementary Figure 2 shows the qPCR results of miR-6126 overexpression in miR-6126 mimic treated ovarian cancer cells (HeyA8, HeyA8-MDR, Skkov3-ip1, SKOV3-TR) Supplementary Figure 3 shows western blotting and qPCR results that shows the ingibition of Integrin beta-1 expression at protein and mRNA level upon miR-6126 mimic treatment. Supplementary Figure 4 shows the size distribution graphs of exosomes isolated from CTL mimic, miR-6126 mimic , CTL inhibitor, miR-6126 inhibitor treated SKOV3-IP1 cells. Supplementary Figure 5 shows ITGB1 mRNA levels in different ovarian cancer exosomes. Supplementary Figure 6 shows in vivo down regulation of ITGB1. Supplementary Table 1 shows demographic information of ovarian cancer patients whose tissue samples used in quantification of miR-6126 expression. Supplementary Table 2 shows raw microarray data for miR-6126 Supplementary Table 3 shows z-score values for miR-6126 for each exosome and cell sample.
Funding
NIH
MD Anderson Cancer Center
History
ARTICLE ABSTRACT
Cancer cells actively promote their tumorigenic behavior by reprogramming gene expression. Loading intraluminal vesicles with specific miRNAs and releasing them into the tumor microenvironment as exosomes is one mechanism of reprogramming whose regulation remains to be elucidated. Here, we report that miR-6126 is ubiquitously released in high abundance from both chemosensitive and chemoresistant ovarian cancer cells via exosomes. Overexpression of miR-6126 was confirmed in healthy ovarian tissue compared with ovarian cancer patient samples and correlated with better overall survival in patients with high-grade serous ovarian cancer. miR-6126 acted as a tumor suppressor by directly targeting integrin-β1, a key regulator of cancer cell metastasis. miR-6126 mimic treatment of cancer cells resulted in increased miR-6126 and decreased integrin-β1 mRNA levels in the exosome. Functional analysis showed that treatment of endothelial cells with miR-6126 mimic significantly reduced tube formation as well as invasion and migration capacities of ovarian cancer cells in vitro. Administration of miR-6126 mimic in an orthotopic mouse model of ovarian cancer elicited a relative reduction in tumor growth, proliferating cells, and microvessel density. miR-6126 inhibition promoted oncogenic behavior by leading ovarian cancer cells to release more exosomes. Our findings provide new insights into the role of exosomal miRNA-mediated tumor progression and suggest a new therapeutic approach to disrupt oncogenic phenotypes in tumors. Cancer Res; 76(24); 7194–207. ©2016 AACR.
