MicroRNA-566 activates EGFR signaling and its inhibition sensitizes glioblastoma cells to nimotuzumab

Molecular Cancer

Research

Tao Jiang¹  Chuan-Bao Zhang¹  Eric J Wagner²  Ling-Chao Chen³  Chun-Sheng Kang⁴  Zhen-Dong Shi⁴  Jian-Ning Zhang⁴  Lei Han⁴  Pei-Yu Pu⁴  Jun-Xia Zhang⁴  Lu-Yue Chen⁴  Kai-Liang Zhang⁵  Xuan Zhou⁶  Ming Yang⁷  Jing-Xuan Yang⁸  Thomas S Frank⁸  Min Li⁸  Yu Ren⁹ 

[1] Beijing Neurosurgical Institute, Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 6 Tiantanxi Li, 100050, Beijing, China;Chinese Glioma Cooperative Group (CGCG), 6 Tiantanxi Li, 100050, Beijing, China;Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, 77030, Houston, TX, USA;Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, 150086, Harbin, China;Chinese Glioma Cooperative Group (CGCG), 6 Tiantanxi Li, 100050, Beijing, China;Department of Neurosurgery, Tianjin Medical University General Hospital; Laboratory of Neuro-Oncology, Tianjin Neurological Institute; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, 300052, Tianjin, China;Chinese Glioma Cooperative Group (CGCG), 6 Tiantanxi Li, 100050, Beijing, China;Department of Neurosurgery, Tianjin Medical University General Hospital; Laboratory of Neuro-Oncology, Tianjin Neurological Institute; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, 300052, Tianjin, China;The Vivian L. Smith Department of Neurosurgery, the University of Texas Medical School at Houston, 77030, Houston, TX, USA;Chinese Glioma Cooperative Group (CGCG), 6 Tiantanxi Li, 100050, Beijing, China;The Department of Otorhinolaryngology and Maxillofacial Oncology, Tianjin Medical University Cancer Institute and Hospital; Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute; National Clinical Research Center of Cancer, 300060, Tianjin, China;The State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 300020, Tianjin, China;The Vivian L. Smith Department of Neurosurgery, the University of Texas Medical School at Houston, 77030, Houston, TX, USA;Tianjin Research Center of Basic Medical Science, Tianjin Medical University, 300070, Tianjin, China;

关键词: EGFR;    Glioblastoma;    miR-566;    Nimotuzumab;    Combination therapy;   

DOI  :  10.1186/1476-4598-13-63

 received in 2013-12-29, accepted in 2014-03-11,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundEpidermal growth factor receptor (EGFR) is amplified in 40% of human glioblastomas. However, most glioblastoma patients respond poorly to anti-EGFR therapy. MicroRNAs can function as either oncogenes or tumor suppressor genes, and have been shown to play an important role in cancer cell proliferation, invasion and apoptosis. Whether microRNAs can impact the therapeutic effects of EGFR inhibitors in glioblastoma is unknown.MethodsmiR-566 expression levels were detected in glioma cell lines, using real-time quantitative RT-PCR (qRT-PCR). Luciferase reporter assays and Western blots were used to validate VHL as a direct target gene of miR-566. Cell proliferation, invasion, cell cycle distribution and apoptosis were also examined to confirm whether miR-566 inhibition could sensitize anti-EGFR therapy.ResultsIn this study, we demonstrated that miR-566 is up-regulated in human glioma cell lines and inhibition of miR-566 decreased the activity of the EGFR pathway. Lentiviral mediated inhibition of miR-566 in glioblastoma cell lines significantly inhibited cell proliferation and invasion and led to cell cycle arrest in the G0/G1 phase. In addition, we identified von Hippel-Lindau (VHL) as a novel functional target of miR-566. VHL regulates the formation of the β-catenin/hypoxia-inducible factors-1α complex under miR-566 regulation.ConclusionsmiR-566 activated EGFR signaling and its inhibition sensitized glioblastoma cells to anti-EGFR therapy.

【 授权许可】

Unknown   
© Zhang et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.