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Open AccessArticle

Knockdown of Musashi RNA Binding Proteins Decreases Radioresistance but Enhances Cell Motility and Invasion in Triple-Negative Breast Cancer

1
Department of Radiation Oncology, University Hospital Münster, 48149 Münster, Germany
2
Department of Gynecology and Obstetrics, University Hospital Münster, 48149 Münster, Germany
3
Medical Oncology Department, National Cancer Institute, Cairo University, 11796 Cairo, Egypt
4
Surgical Oncology Department, National Cancer Institute, Cairo University, 11796 Cairo, Egypt
5
Biotechnology/Biomolecular Chemistry program, Chemistry Department, Faculty of Science, Cairo University, 12613 Giza, Egypt
6
Biomedical Technology Center, Medical Faculty, University of Münster, 48149 Münster, Germany
7
Zoology Department, Faculty of Science, Cairo University, 12613 Giza, Egypt
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(6), 2169; https://doi.org/10.3390/ijms21062169
Received: 29 December 2019 / Revised: 19 March 2020 / Accepted: 19 March 2020 / Published: 21 March 2020
(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)
The therapeutic potential of Musashi (MSI) RNA-binding proteins, important stemness-associated gene expression regulators, remains insufficiently understood in breast cancer. This study identifies the interplay between MSI protein expression, stem cell characteristics, radioresistance, cell invasiveness and migration. MSI-1, MSI-2 and Notch pathway elements were investigated via quantitative polymerase chain reaction (qPCR) in 19 triple-negative breast cancer samples. Measurements were repeated in MDA-MB-231 cells after MSI-1 and -2 siRNA-mediated double knockdown, with further experiments performed after MSI silencing. Flow cytometry helped quantify expression of CD44 and leukemia inhibitory factor receptor (LIFR), changes in apoptosis and cell cycle progression. Proliferation and irradiation-induced effects were assessed using colony formation assays. Radiation-related proteins were investigated via Western blots. Finally, cell invasion assays and digital holographic microscopy for cell migration were performed. MSI proteins showed strong correlations with Notch pathway elements. MSI knockdown resulted in reduction of stem cell marker expression, cell cycle progression and proliferation, while increasing apoptosis. Cells were radiosensitized as radioresistance-conferring proteins were downregulated. However, MSI-silencing-mediated LIFR downregulation resulted in enhanced cell invasion and migration. We conclude that, while MSI knockdown results in several therapeutically desirable consequences, enhanced invasion and migration need to be counteracted before knockdown advantages can be fully exploited. View Full-Text
Keywords: Musashi RNA-binding proteins; breast cancer stem cells; Notch; apoptosis; proliferation; radiotherapy; EGFR; LIFR; migration; invasiveness Musashi RNA-binding proteins; breast cancer stem cells; Notch; apoptosis; proliferation; radiotherapy; EGFR; LIFR; migration; invasiveness
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Troschel, F.M.; Minte, A.; Ismail, Y.M.; Kamal, A.; Abdullah, M.S.; Ahmed, S.H.; Deffner, M.; Kemper, B.; Kiesel, L.; Eich, H.T.; Ibrahim, S.A.; Götte, M.; Greve, B. Knockdown of Musashi RNA Binding Proteins Decreases Radioresistance but Enhances Cell Motility and Invasion in Triple-Negative Breast Cancer. Int. J. Mol. Sci. 2020, 21, 2169.

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