Department of Translation Medicine Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, 310006, China.
Acta Pharmacol Sin. 2021 Aug;42(8):1288-1297. doi: 10.1038/s41401-020-00548-6. Epub 2020 Nov 6.
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 μM) exerted moderate and concentration-dependent inhibition on the cell growth and induced apoptosis, whereas its agonist RAMH (80 μM) 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.
最近的证据表明，组氨酸受体 H3（Hrh3）的表达水平在几种类型的癌症中上调。然而，Hrh3 在非小细胞肺癌（NSCLC）中的作用尚未阐明。在本研究中，我们表明 Hrh3 的表达水平在 NSCLC 样本中显著增加，并且高水平的 Hrh3 与 NSCLC 患者的总体生存（OS）不良相关。在测试的五个人类 NSCLC 细胞系中，Hrh3 明显上调。在 NSCLC 细胞系 H1975、H460 和 A549 中，Hrh3 拮抗剂西普昔芬（CPX，10-80 μM）对细胞生长发挥适度且浓度依赖性抑制作用，并诱导细胞凋亡，而其激动剂 RAMH（80 μM）则逆转了这些作用。此外，通过抑制 EMT 进展，CPX 或 siRNA 抑制 Hrh3 可通过减少 PI3K/Akt/mTOR 和 MEK/ERK 信号通路的磷酸化来抑制 NSCLC 细胞的迁移和侵袭。在携带 H1975 细胞异种移植或 A549 细胞异种移植的裸鼠中，CPX（3mg/kg，每两天一次，腹腔内给药）的给药显著抑制肿瘤生长，增加肿瘤组织中 E-钙粘蛋白和 ZO-1 的表达，减少纤维连接蛋白的表达。总之，这项研究表明 Hrh3 在 NSCLC 的生长和转移中发挥重要作用；它可能是针对肺癌的潜在治疗靶点。
