Yaomin Li1,2, Yawei Liu1,3, Jing Ren4, Shengze Deng1,2, Guozhong Yi1,2, Manlan Guo2, Songren Shu4, Liang Zhao3, Yuping Peng5,6, Songtao Qi7,8. 1. Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838#, Guangzhou, 510515, Guangdong, China. 2. Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. 3. Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou, 510515, Guangdong, China. 4. Southern Medical University, Guangzhou, 510515, Guangdong, China. 5. Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838#, Guangzhou, 510515, Guangdong, China. pyp@fimmu.com. 6. Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. pyp@fimmu.com. 7. Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838#, Guangzhou, 510515, Guangdong, China. qisongtaonfyy@126.com. 8. Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China. qisongtaonfyy@126.com.
Abstract
INTRODUCTION: Temozolomide (TMZ) is the preferred chemotherapeutic drug approved for the Glioblastoma multiforme (GBM) treatment. However, resistance to TMZ is the most intractable challenge for treatment of GBM. Screening of miRNAs is becoming a novel strategy to reveal underlying mechanism of drug-resistance of human tumors. MATERIALS AND METHODS: We conducted RNA sequencing (RNA-seq) for GBM cells treated continuously with TMZ 1 or 2 week or not. Bioinformatic analysis was used to predict targets of these altered miRNAs. Subsequently, we studied the potential role of miR-1268a in TMZ-resistance of GBM cells. RESULTS: Expression levels of 55 miRNAs were identified altering both after 1 and 2 weeks TMZ treatment. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to illuminate the biological implication and related pathways of predicted target genes. We showed that miR-1268a was downregulated after TMZ treatment and targeted ABCC1/MRP1, a membrane transporter contributing to drug resistance, using dual-luciferase assay. Furthermore, we confirmed overexpression of miR-1268a inhibited protein translation of ABCC1 and restored upregulated expression of ABCC1 due to TMZ. Inversely, knockdown of miR-1268a increased ABCC1 at protein level and enhanced upregulation of ABCC1 with TMZ treatment. In addition, our data indicated that miR-1268a enhanced TMZ sensitivity in GBM cells. CONCLUSION: Through RNA-seq analysis, we discovered miR-1268a and elucidated its role in modulating TMZ-resistance of GBM cells by targeting ABCC1.
INTRODUCTION:Temozolomide (TMZ) is the preferred chemotherapeutic drug approved for the Glioblastoma multiforme (GBM) treatment. However, resistance to TMZ is the most intractable challenge for treatment of GBM. Screening of miRNAs is becoming a novel strategy to reveal underlying mechanism of drug-resistance of humantumors. MATERIALS AND METHODS: We conducted RNA sequencing (RNA-seq) for GBM cells treated continuously with TMZ 1 or 2 week or not. Bioinformatic analysis was used to predict targets of these altered miRNAs. Subsequently, we studied the potential role of miR-1268a in TMZ-resistance of GBM cells. RESULTS: Expression levels of 55 miRNAs were identified altering both after 1 and 2 weeks TMZ treatment. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to illuminate the biological implication and related pathways of predicted target genes. We showed that miR-1268a was downregulated after TMZ treatment and targeted ABCC1/MRP1, a membrane transporter contributing to drug resistance, using dual-luciferase assay. Furthermore, we confirmed overexpression of miR-1268a inhibited protein translation of ABCC1 and restored upregulated expression of ABCC1 due to TMZ. Inversely, knockdown of miR-1268a increased ABCC1 at protein level and enhanced upregulation of ABCC1 with TMZ treatment. In addition, our data indicated that miR-1268a enhanced TMZ sensitivity in GBM cells. CONCLUSION: Through RNA-seq analysis, we discovered miR-1268a and elucidated its role in modulating TMZ-resistance of GBM cells by targeting ABCC1.
Authors: Philippe Bertheau; Jacqueline Lehmann-Che; Mariana Varna; Anne Dumay; Brigitte Poirot; Raphaël Porcher; Elisabeth Turpin; Louis-François Plassa; Anne de Roquancourt; Edwige Bourstyn; Patricia de Cremoux; Anne Janin; Sylvie Giacchetti; Marc Espié; Hugues de Thé Journal: Breast Date: 2013-08 Impact factor: 4.380
Authors: Gaspar J Kitange; Ann C Mladek; Brett L Carlson; Mark A Schroeder; Jenny L Pokorny; Ling Cen; Paul A Decker; Wenting Wu; Gwen A Lomberk; Shiv K Gupta; Raul A Urrutia; Jann N Sarkaria Journal: Clin Cancer Res Date: 2012-06-06 Impact factor: 12.531