NDLI: Involvement of Numb-mediated HIF-1 inhibition in anti-proliferative effect of PNA-antimiR-182 in trastuzumab-sensitive and -resistant SKBR3 cells.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Sajadimajd, Soraya Yazdanparast, Razieh Akram, Sadeghirizi
Description	Country affiliation: Iran Author Affiliation: Sajadimajd S ( Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran.); Yazdanparast R ( Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran. ryazdan@ut.ac.ir.); Akram S ( Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran.)
Abstract	Trastuzumab is a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER2) that is overexpressed in about 25 % of breast cancer patients. However, primary and/or acquired resistance to trastuzumab develops in most affected persons. In this study, we explored the functional role of miR-182 inhibition with aiming the sensitization of SKBR3 cells to trastuzumab. Cell viability, apoptosis, colony formation, and migration capacities of SKBR3(S) (sensitive) and SKBR3(R) (resistant) cells were assessed to determine the anti-proliferative effects of PNA-antimiR-182. In addition, the expression levels of miR-182, mRNA of FOXO1, and Bim as well as the protein levels of HER2 and Notch1 signaling factors were evaluated by stem-loop RT-qPCR, RT-qPCR, and Western blot, respectively. The results indicated that miR-182 might play a causal role in the mechanism of trastuzumab. In line with that, PNA-antimiR-182 inhibited synergistically the viability of both the sensitive and resistant cell groups. Furthermore, the inhibitory effect of PNA-anitmiR-182 on migration in SKBR3 cells was more than the induction of apoptosis. In addition, PNA-antimiR-182 reduced the levels of NICD, Hes1, HIF-1 , and p-Akt in both cell groups, while it augmented the intracellular content of FOXO1 and Numb suppressor proteins. In other words, PNA-antimiR-182-mediated upregulation of Numb was associated with downregulation of HIF-1 and Hes1. Consequently, downregulation of miR-182 might find therapeutical value for overcoming trastuzumab resistance. Graphical Abstract The crosstalk between HER2 and Notch1 signaling pathway is mediated by miR-182.
File Format	HTM / HTML
ISSN	10104283
Issue Number	4
Journal	Tumor Biology
Volume Number	37
e-ISSN	14230380
Language	English
Publisher	Springer
Publisher Date	2016-04-01
Publisher Place	Netherlands
Access Restriction	Subscribed
Content Type	Text
Resource Type	Article
Subject	Medicine Cancer Research

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