Blockage of a miR-21/EGFR regulatory feedback loop augments anti-EGFR therapy in glioblastomas

Kai-Liang Zhang; Lei Han; Lu-Yue Chen; Zhen-Dong Shi; Ming Yang; Yu Ren; Ling-Chao Chen; Jun-Xia Zhang; Pei-Yu Pu; Chun-Sheng Kang

doi:10.1016/j.canlet.2013.08.043

Blockage of a miR-21/EGFR regulatory feedback loop augments anti-EGFR therapy in glioblastomas

Cancer Lett. 2014 Jan 1;342(1):139-49. doi: 10.1016/j.canlet.2013.08.043. Epub 2013 Sep 3.

Authors

Kai-Liang Zhang¹, Lei Han, Lu-Yue Chen, Zhen-Dong Shi, Ming Yang, Yu Ren, Ling-Chao Chen, Jun-Xia Zhang, Pei-Yu Pu, Chun-Sheng Kang

Affiliation

¹ 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.

PMID: 24012640
DOI: 10.1016/j.canlet.2013.08.043

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.

Keywords: EGFR; Feedback loop; Glioblastoma; miR-21.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Animals
Antibodies, Monoclonal, Humanized / pharmacology
Antibodies, Monoclonal, Humanized / therapeutic use
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Base Sequence
Binding Sites
Brain Neoplasms / drug therapy
Brain Neoplasms / metabolism*
Brain Neoplasms / pathology
Cell Line, Tumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism*
Feedback, Physiological
Gene Expression Regulation, Neoplastic
Glioblastoma / drug therapy
Glioblastoma / metabolism*
Glioblastoma / pathology
Humans
Mice
Mice, Nude
MicroRNAs / genetics*
Neoplasm Invasiveness
PPAR alpha / genetics
PPAR alpha / metabolism
Proto-Oncogene Proteins c-akt / metabolism
RNA Interference
Transcription Factor AP-1 / metabolism
Tumor Burden
Von Hippel-Lindau Tumor Suppressor Protein / metabolism
Wnt Signaling Pathway
Xenograft Model Antitumor Assays
beta Catenin / metabolism

Substances

3' Untranslated Regions
Antibodies, Monoclonal, Humanized
Antineoplastic Agents
CTNNB1 protein, human
MIRN21 microRNA, human
MicroRNAs
PPAR alpha
Transcription Factor AP-1
beta Catenin
nimotuzumab
Von Hippel-Lindau Tumor Suppressor Protein
EGFR protein, human
ErbB Receptors
Proto-Oncogene Proteins c-akt
VHL protein, human