Activation of histamine H4 receptor suppresses the proliferation and invasion of esophageal squamous cell carcinoma via both metabolism and non-metabolism signaling pathways
Activation of histamine H4 receptor suppresses the proliferation and invasion of esophageal squamous cell carcinoma via both metabolism and non-metabolism signaling pathways
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组胺H-4受体激活通过代谢和非代谢信号通路抑制食管鳞癌的增殖和侵袭
DOI：
10.1007/s00109-018-1676-z
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发表时间：
2018-09-01
影响因子：
4.7
通讯作者：
Cai, Wen-Ke
中科院分区：
文献类型：
--
作者：
He, Gong-Hao;Ding, Jia-Qi;Cai, Wen-Ke
虽然组胺H-4受体（H4 R）的失调在消化道肿瘤中被广泛和频繁地报道，并且与这些肿瘤的恶性和增殖相关，但H4 R在食管鳞状细胞癌（ESCC）中的存在及其病理生理功能仍然未知。在本研究中，我们探讨了H4 R在人食管鳞癌样本和细胞系中的表达和功能。H4 R在低分化ESCC样本和细胞系中过表达，并与ESCC患者的中位生存期相关。H4 R的激活不仅显著地阻断了细胞增殖、细胞周期和侵袭，而且还抑制了TE-2异种移植物的生长并增加了异种移植物荷瘤小鼠的存活。根据机制实验，代谢（乙酰辅酶A合成酶2（ACSS 2））和非代谢（丝裂原活化蛋白激酶（MAPK））相关的途径参与了H4 R激活抑制肿瘤增殖和侵袭的作用。基于这些发现，H4 R在食管癌中过表达并对ESCC的增殖和侵袭具有抗肿瘤作用，H4 R在食管鳞癌中的作用及其机制研究表明，H4 R的表达与食管鳞癌细胞分化和患者生存期有关，代谢型（ACSS 2）和非代谢型（MAPK）-本研究为H4 R与ESCC的关系提供了新的视角，H4 R可能成为ESCC治疗的新靶点。
Although dysregulation of histamine H-4 receptor (H4R) has widely and frequently been documented in digestive carcinomas and correlates with the malignancy and proliferation of these tumors, the existence of H4R and its pathophysiological function in esophageal squamous cell carcinoma (ESCC) remains unknown. In our present study, we explored the expression and function of H4R in human ESCC samples and cell lines. H4R was overexpressed in poorly differentiated ESCC samples and cell lines and correlated with the median survival of ESCC patients. H4R activation not only significantly blocked cell proliferation, cell cycle, and invasion but also inhibited the growth of TE-2 xenografts and increased the survival of xenograft-bearing mice. According to the mechanistic experiments, both metabolism (acetyl-coenzyme A synthetase 2 (ACSS2))- and non-metabolism (mitogen-activated protein kinase (MAPK))-related pathways were involved in the effect of H4R activation on suppressing tumor proliferation and invasion. Based on these findings, H4R was overexpressed in esophageal cancer and exerted antitumor effects on ESCC proliferation and invasion, suggesting that H4R may be a novel potential target of therapies for ESCC.Key messagesThe function of H4R in ESCC and the underlying mechanisms were investigated.H4R expression was correlated with ESCC cell differentiation and patients' survival.Both metabolism (ACSS2) and non-metabolism (MAPK)-related pathways were involved.This study provided new insight into the relationship between H4R and ESCC.H4R may be a novel potential therapeutic target for ESCC.