Inhibition of histamine receptor 3 suppresses glioblastoma tumor growth, invasion, and epithelial-to-mesenchymal transition
| Autor: | Tian-Zhi Zhao, Zhuyi Li, Yu-Qiao Xu, Ting Chang, Wen-Ke Cai, Zhuo Zhang, Chao Sun, Yong-Xiang Yang, Jia-Ji Lin |
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| Rok vydání: | 2015 |
| Předmět: |
MAPK/ERK pathway
Small interfering RNA Epithelial-Mesenchymal Transition Blotting Western Vimentin Real-Time Polymerase Chain Reaction Mice Histamine receptor histamine receptor 3 Glioma medicine Animals Humans Receptors Histamine H3 Neoplasm Invasiveness Epithelial–mesenchymal transition Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation biology Brain Neoplasms glioblastoma invasion medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays Molecular biology Rats Up-Regulation Oncology biology.protein epithelial-to-mesenchymal transition Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.3672 |
| Popis: | // Jia-Ji Lin 1, * , Tian-Zhi Zhao 2, * , Wen-Ke Cai 3, * , Yong-Xiang Yang 1 , Chao Sun 1 , Zhuo Zhang 1 , Yu-Qiao Xu 4 , Ting Chang 1 , Zhu-Yi Li 1 1 Department of Neurology, Tangdu Hospital, The Fourth Military Medical University, Xi’an, China 2 Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, China 3 Department of Cardio-Thoracic Surgery, Kunming General Hospital of Chengdu Military Region, Kunming, China 4 Department of Pathology, The Fourth Military Medical University, Xi’an, China * These authors have contributed equally to this work Correspondence to: Zhu-Yi Li, e-mail: lizhuyi126@126.com Ting Chang, e-mail: tdchangting126@126.com Keywords: histamine receptor 3, glioblastoma, epithelial-to-mesenchymal transition, invasion Received: January 25, 2015 Accepted: March 24, 2015 Published: April 10, 2015 ABSTRACT Histamine receptor 3 (H3R) is expressed in various tumors and correlated with malignancy and tumor proliferation. However, the role of H3R in tumor invasion and epithelial to mesenchymal transition (EMT) remains unknown. Here, we explored the H3R in the highly invasive glioblastoma (GBM) and U87MG cells. We found that H3R mRNA and protein levels were up-regulated in the GBM and glioma cell lines compared to normal brain tissue and astrocytes. In U87MG cell line, inhibition of H3R by siRNA or the antagonist ciproxifan (CPX) suppressed proliferation, invasiveness, and the expression of EMT activators (Snail, Slug and Twist). In addition, expression of epithelial markers (E-cadherin and ZO-1) was up-regulated and expression of mesenchymal markers (vimentin and N-cadherin) was down-regulated in vitro and in vivo in a xenograft model. In addition, we also showed that inhibition of H3R by siRNA or CPX inactivated the PI3K/Akt and MEK/ERK signaling pathways, while inhibition of Akt or ERK activity with antagonists or siRNAs suppressed H3R agonist ( R )-(α)-(-)- methylhistamine dihydrobromide (RAMH) mediated invasion and reorganization of cadherin-household. In conclusion, overexpression of H3R is associated with glioma progression. Inhibition of H3R leads to suppressed invasion and EMT of GBM by inactivating the PI3K/Akt and MEK/ERK pathways in gliomas. |
| Databáze: | OpenAIRE |
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