title: Inhibition of cancer stem cell-like properties and reduced chemoradioresistance of glioblastoma using microRNA145 with cationic polyurethane-short branch PEI.
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.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Yang
authors.forename: Yueh
authors.initials: Y
authors.lastname: Chien
authors.forename: Guang-Yuh
authors.initials: GY
authors.lastname: Chiou
authors.forename: Jong-Yuh
authors.initials: JY
authors.lastname: Cherng
authors.forename: Mong-Lien
authors.initials: ML
authors.lastname: Wang
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Lo
authors.forename: Yuh-Lih
authors.initials: YL
authors.lastname: Chang
authors.forename: Pin-I
authors.initials: PI
authors.lastname: Huang
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Chen
authors.forename: Yang-Hsin
authors.initials: YH
authors.lastname: Shih
authors.forename: Ming-Teh
authors.initials: MT
authors.lastname: Chen
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018014:Gene Transfer Techniques; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D011094:Polyethyleneimine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D011140:Polyurethanes / Q000138:chemical synthesis / Q000737:chemistry*; D011836:Radiation Tolerance / Q000187:drug effects; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D000077204:Temozolomide
chemical_list: D020413:3' Untranslated Regions; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D011140:Polyurethanes; D055748:SOXB1 Transcription Factors; D003606:Dacarbazine; D011094:Polyethyleneimine; D000077204:Temozolomide