MiR-203 downregulation is responsible for chemoresistance in human glioblastoma by promoting epithelial-mesenchymal transition via SNAI2

// Hongzhan Liao 1,* , Yifeng Bai 2,* , Shengcong Qiu 1 , Lei Zheng 3 , Lianyan Huang 4 , Tianzhu Liu 1 , Xin Wang 1 , Yanting Liu 1 , Ningbo Xu 1 , Xiaohui Yan 5 and Hongbo Guo 1 1 Department of Neurosurgery, Neurosurgery Institute of Guangdong, Key Laboratory on Brain Function Repair and Regeneration of Guangdong, Zhujiang Hospital, Southern Medical University, Guangzhou, China 2 Department of Oncology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, China 3 Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China 4 School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, China 5 Research Center of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China * These authors contributed equally to this work Correspondence to: Hongbo Guo, email: // Keywords : chemotherapy resistance, epithelial-mesenchymal transition, microRNAs, glioblastoma, SNAI2 Received : January 16, 2015 Accepted : February 10, 2015 Published : March 12, 2015 Abstract Epithelial-mesenchymal transition (EMT) has been recognized as a key element of cell migration, invasion, and drug resistance in several types of cancer. In this study, our aim was to clarify microRNAs (miRNAs)-related mechanisms underlying EMT followed by acquired resistance to chemotherapy in glioblastoma (GBM). We used multiple methods to achieve our goal including microarray analysis, qRT-PCR, western blotting analysis, loss/gain-of-function analysis, luciferase assays, drug sensitivity assays, wound-healing assay and invasion assay. We found that miR-203 expression was significantly lower in imatinib-resistant GBM cells (U251AR, U87AR) that underwent EMT than in their parental cells (U251, U87). Ectopic expression of miR-203 with miRNA mimics effectively reversed EMT in U251AR and U87AR cells, and sensitized them to chemotherapy, whereas inhibition of miR-203 in the sensitive lines with antisense oligonucleotides induced EMT and conferred chemoresistance. SNAI2 was identified as a direct target gene of miR-203. The knockdown of SNAI2 by short hairpin RNA (shRNA) inhibited EMT and drug resistance. In GBM patients, miR-203 expression was inversely related to SNAI2 expression, and those tumors with low expression of miR-203 experienced poorer clinical outcomes. Our findings indicate that re-expression of miR-203 or targeting SNAI2 might serve as potential therapeutic approaches to overcome chemotherapy resistance in GBM.