Inhibition of cancer stem cell-like properties and reduced chemoradioresistance of glioblastoma using microRNA145 with cationic polyurethane-short branch PEI

详细信息    查看全文

• 作者：Yi-Ping Yang^a ; ¹ ; Yueh Chien^b ; ^f ; ² ; Guang-Yuh Chiou^b ; ^f ; ¹ ; Jong-Yuh Cherng^e ; ² ; Mong-Lien Wang^c ; Wen-Liang Lo^d ; ^f ; Yuh-Lih Chang^b ; ^g ; Pin-I Huang^a ; ^h ; Yi-Wei Chen^a ; ^h ; Yang-Hsin Shih^c ; ⁱ ; Ming-Teh Chen^c ; ⁱ ; Shih-Hwa Chiou^a ; ^b ; ^c ; ^f ; ^{shchiou@vghtpe.gov.tw}
• 关键词：Glioblastoma ; Drug-resistance ; miR145 ; Polyurethane-short branch polyethylenimine
• 刊名：Biomaterials
• 出版年：2012
• 出版时间：February, 2012
• 年：2012
• 卷：33
• 期：5
• 页码：1462-1476
• 全文大小：1K

文摘

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^{?/sup>-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.}