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    The effects of chitosan/miR-200c nanoplexes on different stages of cancers in breast cancer cell lines
    (Elsevier Science Bv, 2016) Kaban, Kubra; Salva, Emine; Akbuga, Julide
    Dysregulation of miR-200c in breast cancer has been associated with migration, epithelial mesenchymal transition (EMT), angiogenesis and metastasis of the tumor cells. Therefore, the modulation of miR-200c offers a promising therapeutic approach in breast cancer. However, the major obstacles in the usage of miRNAs in therapy are their low stability, rapid clearance, and poor cellular uptake. The development of efficient and safe delivery systems is important in effective therapy with miRNA. The purpose of this study was to investigate the therapeutic role of chitosan/miR-200c nanoplexes in angiogenesis, EMT, invasion, and apoptosis in breast cancer cell lines. We found that miR-200c levels were downregulated in various breast cancer cell lines by qRT-PCR After transfection with chitosan/miRNA nanoplexes in the appropriate size (294 nm) and zeta potential (12.3 mV), levels of miR-200c increased and reached the endogenous miR-200c levels in the MCF-7, MDA-MB-231, and MDA-MB-435 cells. While the chitosan/miR-200c nanoplexes decreased angiogenesis, invasion, EMT, and metastasis in the cells, the apoptosis levels increased by 3.1, 1.3, and 3 fold in the MCF-7, MDA-MB-231, MDA-MB-435 cell lines, respectively. Consequently, chitosan is a suitable carrier for miR-200c and formed stable nanoplexes with miR-200c. The effect of the chitosan/miRNA nanoplexes on tumor angiogenesis, EMT, invasion, metastasis, and apoptosis, changed depending on the cell-types. Therefore, during the treatment with the chitosan based miR-200c nanoplexes in breast cancers, the type of tumor cells must be considered. (C) 2016 Elsevier B.V. All rights reserved.
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    In Vitro Dose Studies on Chitosan Nanoplexes for microRNA Delivery in Breast Cancer Cells
    (Mary Ann Liebert, Inc, 2017) Kaban, Kubra; Salva, Emine; Akbuga, Julide
    Changes in microRNA (miRNA) expression levels that play important roles in regulation lead to many pathological events such as cancer. The miR-200 family is an important target in cancer therapy. The aim of this study is to equilibrate endogenous levels between cancer and noncancerous cells to prevent serious side effects of miR-200c- and miR-141-like metastatic colonization. For the first time, the characterization of miR-200c and miR-141 cluster containing chitosan nanoplexes was shown, and the optimization of miRNA expression levels by conducting dose studies in breast cancer cell lines was made. The mean diameter of chitosan/miR-141 and chitosan/miR-200c nanoplexes ranged from 296 to 355 nm and from 294 to 380 nm depending on the N/P ratio, respectively. The surface charge of nanoplexes was positive with zeta potential of +12 to +26 mV. While naked miRNA was degraded after 0 min in a 10% serum-containing medium, chitosan/miRNA nanoplexes were protected for 72 h. During the in vitro cellular uptake study, nanoplexes were observed to be accumulating in the cytoplasm or nucleus. After using different doses for miR-200c, the determined doses are 750, 100, and 750 ng in the MCF-7, MDA-MB-231, and MDA-MB-435 cell lines, respectively. Doses were determined as 100 ng for MDA-MB-231 and 150 ng for MDA-MB-435 to reach endogenous miR-141 levels of MCF-10A. Our results suggest that chitosan nanoplexes for miR-200c and miR-141 are an efficient delivery system in terms of formulation and transfection. As a conclusion, dose studies are important to provide effective treatment with miRNAs.
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    Modulation of the dual-faced effects of miR-141 with chitosan/miR-141 nanoplexes in breast cancer cells
    (Wiley, 2019) Kaban, Kubra; Salva, Emine; Akbuga, Julide
    Background miR-141, known as a tumor suppressive microRNA, is downregulated in breast cancer. However, recent contrasting studies report that it also acts as oncogene when it is upregulated. The present study aimed to investigate whether miR-141 is a tumor suppressor or oncogenic when it reaches normal levels in chitosan/miR-141 nanoplexes. Methods Chitosan nanoplexes were prepared using simple complexation method. Nanoplexes were characterized by a gel retardation assay and zeta potential and particle size measurements. To determine the expression level of miR-141, a quantitative real-time polymerase chain reaction was performed. The effects of miR-141 mimics were investigated with respect to angiogenesis by vascular endothelial growth factor (VEGF), epithelial-mesenchymal transition (EMT) by E-cadherin, metastasis by Igfbp-4 and Tinagl1 enzyme-linked immunosorbent assays, invasion by an invasion chamber, and apoptosis by Annexin V. Results The miR-141 expression levels of MDA-MB-231 and MDA-MB-435 cells by administration of chitosan/mimic miR-141 nanoplexes reached endogenous miR-141 levels of a non-tumorigenic epithelial breast cell line, MCF-10A. According to our results, metastasis, VEGF, EMT and invasion in breast cancer cells were diminished, whereas apoptosis increased by 1.5- and 2.4-fold in breast cancer cell lines as a result of the miR-141 mimics. Conclusions In conclusion, we have demonstrated that administration of miR-141 mimics at the determined doses to breast cancer cells revealed a tumor suppressor effect, and not the oncogenic face. The delivery of miR-141 by chitosan nanoplexes presents a promising approach for the suppression of breast cancer.