Oncotarget

Research Papers:

Inhibition of histamine receptor 3 suppresses glioblastoma tumor growth, invasion, and epithelial-to-mesenchymal transition

Jia-Ji Lin _, Tian-Zhi Zhao, Wen-Ke Cai, Yong-Xiang Yang, Chao Sun, Zhuo Zhang, Yu-Qiao Xu, Ting Chang and Zhu-Yi Li

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Oncotarget. 2015; 6:17107-17120. https://doi.org/10.18632/oncotarget.3672

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Abstract

Jia-Ji Lin1,*, Tian-Zhi Zhao2,*, Wen-Ke Cai3,*, Yong-Xiang Yang1, Chao Sun1, Zhuo Zhang1, Yu-Qiao Xu4, Ting Chang1, Zhu-Yi Li1

1Department of Neurology, Tangdu Hospital, The Fourth Military Medical University, Xi’an, China

2Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, China

3Department of Cardio-Thoracic Surgery, Kunming General Hospital of Chengdu Military Region, Kunming, China

4Department 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.


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