title: Blockage of a miR-21/EGFR regulatory feedback loop augments anti-EGFR therapy in glioblastomas.
abstract: Epidermal growth factor receptors (EGFR) expression is frequently amplified in human glioblastoma cells. Nimotuzumab, a monoclonal antibody (mAb) against EGFR, has been used globally in clinics as an anti-cancer agent. It is largely unknown whether the blockade of miR-21, a microRNA that is upregulated in glioma cells, could amplify the effects of nimotuzumab. Herein, we have demonstrated that miR-21 directly targets von Hippel-Lindau (VHL) and peroxisome-proliferator-activated receptor α (PPARα) and that miR-21 regulates EGFR/AKT signaling through VHL/β-catenin and the PPARα/AP-1 axis. Further, the expression of miR-21 is regulated by EGFR via the activation of β-catenin and AP-1. These data indicate that a feedback loop exists between miR-21 and EGFR. We also show that the combination of nimotuzumab and an inhibitor of miR-21 is superior to single-agent therapy. These results clarify a novel association between miR-21 and EGFR in the regulation of cancer cell progression.
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin 300052, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China; Chinese Glioma Cooperative Group (CGCG), China.
authors.forename: Kai-Liang
authors.initials: KL
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.forename: Lu-Yue
authors.initials: LY
authors.lastname: Chen
authors.forename: Zhen-Dong
authors.initials: ZD
authors.lastname: Shi
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: Ren
authors.forename: Ling-Chao
authors.initials: LC
authors.lastname: Chen
authors.forename: Jun-Xia
authors.initials: JX
authors.lastname: Zhang
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Pu
authors.forename: Chun-Sheng
authors.initials: CS
authors.lastname: Kang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D001665:Binding Sites; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D018808:Transcription Factor AP-1 / Q000378:metabolism; D047368:Tumor Burden; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D047493:PPAR alpha; D018808:Transcription Factor AP-1; D051176:beta Catenin; C501466:nimotuzumab; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C497446:VHL protein, human
keywords: EGFR; Feedback loop; Glioblastoma; miR-21