Lin Jia-Ji, Zhao Tian-Zhi, Cai Wen-Ke, Yang Yong-Xiang, Sun Chao, Zhang Zhuo, Xu Yu-Qiao, Chang Ting, Li Zhu-Yi
Department of Neurology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Oncotarget. 2015 Jul 10;6(19):17107-20. doi: 10.18632/oncotarget.3672.
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.
组胺受体3（H3R）在多种肿瘤中表达，并与恶性肿瘤和肿瘤增殖相关。然而，H3R在肿瘤侵袭和上皮-间质转化（EMT）中的作用仍不清楚。在此，我们对高侵袭性胶质母细胞瘤（GBM）和U87MG细胞中的H3R进行了研究。我们发现，与正常脑组织和星形胶质细胞相比，GBM和胶质瘤细胞系中H3R的mRNA和蛋白水平上调。在U87MG细胞系中，通过小干扰RNA（siRNA）或拮抗剂西普罗芬（CPX）抑制H3R可抑制细胞增殖、侵袭以及EMT激活因子（Snail、Slug和Twist）的表达。此外，在异种移植模型的体内和体外实验中，上皮标志物（E-钙黏蛋白和ZO-1）的表达上调，间充质标志物（波形蛋白和N-钙黏蛋白）的表达下调。此外，我们还表明，通过siRNA或CPX抑制H3R可使PI3K/Akt和MEK/ERK信号通路失活，而用拮抗剂或siRNAs抑制Akt或ERK活性可抑制H3R激动剂（R）-（α）-（-）-甲基组胺二氢溴化物（RAMH）介导的侵袭和钙黏蛋白家族的重组。总之，H3R的过表达与胶质瘤进展相关。抑制H3R可通过使胶质瘤中的PI3K/Akt和MEK/ERK通路失活，从而抑制GBM的侵袭和EMT。
