Inhibition of histamine receptor H3 suppresses the growth and metastasis of human non-small cell lung cancer cells via inhibiting PI3K/Akt/mTOR and MEK/ERK signaling pathways and blocking EMT
Inhibition of histamine receptor H3 suppresses the growth and metastasis of human non-small cell lung cancer cells via inhibiting PI3K/Akt/mTOR and MEK/ERK signaling pathways and blocking EMT
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抑制组胺受体H3通过抑制PI3K/Akt/mTOR和MEK/ERK信号通路并阻断EMT来抑制人非小细胞肺癌细胞的生长和转移
DOI：
10.1038/s41401-020-00548-6
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发表时间：
2020-11-06
影响因子：
8.2
通讯作者：
Zhang, Shi-rong
中科院分区：
文献类型：
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作者：
Zhao, Yan-yan;Jia, Jing;Zhang, Shi-rong
最近的证据表明，组胺受体H3（Hrh 3）的表达水平在几种类型的癌症中上调。然而，Hrh 3在非小细胞肺癌（NSCLC）中的作用尚未阐明。在本研究中，我们发现Hrh 3的表达水平在NSCLC样本中显著增加，并且高水平的Hrh 3与NSCLC患者的总生存率（OS）差相关。在测试的五种人NSCLC细胞系中，Hrh 3显著上调。在NSCLC细胞系H1975、H460和A549中，Hrh 3拮抗剂ciproxifan（CPX，10-80 μ M）对细胞生长产生中度和浓度依赖性抑制并诱导凋亡，而其激动剂RAMH（80 μ M）逆转这些作用。CPX或siRNA对Hrh 3的抑制可通过降低PI 3 K/Akt/mTOR和MEK/ERK信号通路的磷酸化水平，抑制上皮间质转化（EMT）进程，从而延缓NSCLC细胞的迁移和侵袭。在荷瘤裸鼠中，CPX（3 mg/kg，隔日一次，腹腔注射）能显著抑制肿瘤生长，并能增加肿瘤组织中E-cadherin和ZO-1的表达，降低Fibronectin的表达。结论：Hrh 3在NSCLC的生长和转移中起重要作用，可能成为肺癌治疗的潜在靶点。
Recent evidence shows that the expression levels of histamine receptor H3 (Hrh3) are upregulated in several types of cancer. However, the role of Hrh3 in non-small cell lung cancer (NSCLC) has not been elucidated. In the present study, we showed that the expression levels of Hrh3 were significantly increased in NSCLC samples, and high levels of Hrh3 were associated with poor overall survival (OS) in NSCLC patients. In five human NSCLC cell lines tested, Hrh3 was significantly upregulated. In NSCLC cell lines H1975, H460, and A549, Hrh3 antagonist ciproxifan (CPX, 10-80 mu M) exerted moderate and concentration-dependent inhibition on the cell growth and induced apoptosis, whereas its agonist RAMH (80 mu M) reversed these effects. Furthermore, inhibition of Hrh3 by CPX or siRNA retarded the migration and invasion of NSCLC cells through inhibiting epithelial-mesenchymal transition (EMT) progression via reducing the phosphorylation of PI3K/Akt/mTOR and MEK/ERK signaling pathways. In nude mice bearing H1975 cell xenograft or A549 cell xenograft, administration of CPX (3 mg/kg every other day, intraperitoneal) significantly inhibited the tumor growth with increased E-cadherin and ZO-1 expression and decreased Fibronectin expression in tumor tissue. In conclusion, this study reveals that Hrh3 plays an important role in the growth and metastasis of NSCLC; it might be a potential therapeutic target against the lung cancer.