Inhibition of cancer stem cell-like properties and reduced chemoradioresistance of glioblastoma using microRNA145 with cationic polyurethane-short branch PEI |
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Authors: | Yang Yi-Ping Chien Yueh Chiou Guang-Yuh Cherng Jong-Yuh Wang Mong-Lien Lo Wen-Liang Chang Yuh-Lih Huang Pin-I Chen Yi-Wei Shih Yang-Hsin Chen Ming-Teh Chiou Shih-Hwa |
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Institution: | a Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan b Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan c School of Medicine, National Yang-Ming University, Taipei, Taiwan d Department of Dentistry, Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan e Department of Chemistry and Biochemistry, National Chung Cheng University, Taipei Veterans General Hospital, Taipei, Taiwan f Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan g Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan h Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan i Department of Neurosurgery, Taipei Veterans General Hospital, Taipei, Taiwan |
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Abstract: | Glioblastomas (GBMs) are the most common primary brain tumors with poor prognosis. CD133 has been considered a putative marker of cancer stem cells (CSCs) in malignant cancers, including GBMs. MicroRNAs (miRNAs), highly conserved small RNA molecules, may target oncogenes and have potential as a therapeutic strategy against cancer. However, the role of miRNAs in GBM-associated CSCs remains mostly unclear. In this study, our miRNA/mRNA-microarray and RT-PCR analysis showed that the expression of miR145 (a tumor-suppressive miRNA) is inversely correlated with the levels of Oct4 and Sox2 in GBM-CD133+ cells and malignant glioma specimens. We demonstrated that miR145 negatively regulates GBM tumorigenesis by targeting Oct4 and Sox2 in GBM-CD133+. Using polyurethane-short branch polyethylenimine (PU-PEI) as a therapeutic-delivery vehicle, PU-PEI-mediated miR145 delivery to GBM-CD133+ significantly inhibited their tumorigenic and CSC-like abilities and facilitated their differentiation into CD133−-non-CSCs. Furthermore, PU-PEI-miR145-treated GBM-CD133+ effectively suppressed the expression of drug-resistance and anti-apoptotic genes and increased the sensitivity of the cells to radiation and temozolomide. Finally, the in vivo delivery of PU-PEI-miR145 alone significantly suppressed tumorigenesis with stemness, and synergistically improved the survival rate when used in combination with radiotherapy and temozolomide in orthotopic GBM-CD133+-transplanted immunocompromised mice. Therefore, PU-PEI-miR145 is a novel therapeutic approach for malignant brain tumors. |
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Keywords: | Glioblastoma Drug-resistance miR145 Polyurethane-short branch polyethylenimine |
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