The HRH4 rs11662595 mutation is associated with histamine H4 receptor dysfunction and with increased epithelial-to-mesenchymal transition progress in non-small cell lung cancer
The HRH4 rs11662595 mutation is associated with histamine H4 receptor dysfunction and with increased epithelial-to-mesenchymal transition progress in non-small cell lung cancer
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HRH4 rs11662595 突变与组胺 H-4 受体功能障碍以及非小细胞肺癌中上皮间质转化进展增加相关
DOI：
10.1016/j.bbadis.2017.08.018
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发表时间：
2017-11-01
影响因子：
6.2
通讯作者：
He, Gong-Hao
中科院分区：
文献类型：
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作者：
Cai, Wen-Ke;Zhang, Jia-Bin;He, Gong-Hao
我们以前证明组胺H-4受体（HRH 4）在抑制非小细胞肺癌（NSCLC）上皮间质转化（EMT）过程中发挥重要作用。此外，最近的研究表明，HRH 4基因的遗传变异影响HRH 4的功能，并最终导致某些HRH 4相关疾病。然而，HRH 4基因多态性与非小细胞肺癌的关系及其机制尚不清楚。本研究旨在探讨HRH 4基因rs 11662595多态性对HRH 4基因功能的影响及其与非小细胞肺癌的关系。对于基础实验，用野生型或rs 11662595突变的HRH 4克隆转染A549细胞，并进行体外和体内实验。我们发现rs 11662595显著降低HRH 4激活Gi蛋白的能力，这导致促进EMT进展、细胞增殖和体外侵袭行为。此外，体内实验还表明，rs 11662595减弱了HRH 4激动剂在接种nu/nu小鼠中的抗EMT作用。在临床实验方面，我们在624例NSCLC患者中进行了前瞻性队列研究，进一步证明了rs 11662595与NSCLC的预后、恶性程度和转移有关。结论：rs 11662595是一个导致HRH 4功能障碍的功能缺失的多态性位点，并可减弱HRH 4在NSCLC中的抗EMT功能，这为NSCLC的预后和治疗提供了一个有前景的生物标志物。
We previously demonstrated that histamine H-4 receptor (HRH4) played important roles to suppress epithelial-to-mesenchymal transition (EMT) progress in non-small cell lung cancer (NSCLC). Furthermore, recent investigations suggested that genetic variations in HRH4 gene affected HRH4 function and eventually contributed to certain HRH4-related diseases. However, the relations between polymorphisms in HRH4 gene and NSCLC as well as their underlying mechanisms remain largely uninvestigated. This study aims to investigate the genetic effect of a nonsynonymous HRH4 polymorphism (rs11662595) on HRH4 function and its association with NSCLC both basically and clinically. For basic experiments, A549 cells were transfected with either wild type or rs11662595 mutated HRH4 clone and subjected to both in vitro and in vivo experiments. We showed that rs11662595 significantly decreased the ability of HRH4 to activate Gi protein, which resulted in facilitation of EMT progress, cell proliferation, and invasion behavior in vitro. Moreover, in vivo experiments also showed that rs11662595 attenuated the anti-EMT effects of HRH4 agonist in inoculated nu/nu mice. For clinical experiments, we performed a prospective cohort study among 624 NSCLC patients and further proved that rs11662595 was responsible for the prognosis, degree of malignancy and metastasis of NSCLC. In conclusion, these findings reveal that rs11662595 is a loss-of-function polymorphism that results in dysfunction of HRH4 and attenuates the anti EMT function of HRH4 in NSCLC, which provides a promising biomarker for prognosis and therapy of NSCLC.