Inhibition of histamine receptor 3 suppresses glioblastoma tumor growth, invasion, and epithelial-to-mesenchymal transition.
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.
Department of Neurology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Jia-Ji
JJ
Lin
Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Tian-Zhi
TZ
Zhao
Department of Cardio-Thoracic Surgery, Kunming General Hospital of Chengdu Military Region, Kunming, China.
Wen-Ke
WK
Cai
Department of Neurology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Yong-Xiang
YX
Yang
Department of Neurology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Chao
C
Sun
Department of Neurology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Zhuo
Z
Zhang
Department of Pathology, The Fourth Military Medical University, Xi'an, China.
Yu-Qiao
YQ
Xu
Department of Neurology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Ting
T
Chang
Department of Neurology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Zhu-Yi
ZY
Li
D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology*; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D018100:Receptors, Histamine H3
epithelial-to-mesenchymal transition; glioblastoma; histamine receptor 3; invasion