Cheng Qijian, Zhou Ling, Zhou Jianping, Wan Huanying, Li Qingyun, Feng Yun
Department of Respiration, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China.
Oncol Rep. 2016 Sep;36(3):1403-10. doi: 10.3892/or.2016.4967. Epub 2016 Jul 22.
Angiotensin II (AngII) is a multifunctional bioactive peptide in the renin-angiotensin system (RAS). Angiotensin-converting enzyme 2 (ACE2) is a newly identified component of RAS. We previously reported that ACE2 overexpression may inhibit cell growth and vascular endothelial growth factor (VEGF) production in vitro and in vivo. In the present study, we investigated the effect of ACE2 on tumor-associated angiogen-esis after the development of acquired platinum resistance in non-small cell lung cancer (NSCLC). Four NSCLC cell lines, A549, LLC, A549-DDP and LLC-DDP, were used in vitro, while A549 and A549-DDP cells were used in vivo. A549-DDP and LLC-DDP cells were newly established at our institution as acquired platinum-resistant sublines by culturing the former parent cells in cisplatin (CDDP)-containing conditioned medium for 6 months. These platinum-resistant cells showed significantly higher angiotensin II type 1 receptor (AT1R), ACE and VEGF production and lower ACE2 expression than their corresponding parent cells. We showed that ACE2 overexpression inhibited the production of VEGF in vitro and in vivo compared to their corresponding parent cells. We also found that ACE2 overexpression reduced the expression of AT1R and ACE. Additionally, we confirmed that ACE2 overexpres-sion inhibited cell growth and VEGF production while simultaneously suppressing ACE and AT1R expression in human lung cancer xenografts. Our findings indicate that ACE2 overexpression may potentially suppress angiogenesis in NSCLC after the development of acquired platinum resistance.
血管紧张素II（AngII）是肾素-血管紧张素系统（RAS）中的一种多功能生物活性肽。血管紧张素转换酶2（ACE2）是RAS新发现的一个组分。我们之前报道过ACE2过表达在体外和体内可能抑制细胞生长及血管内皮生长因子（VEGF）的产生。在本研究中，我们调查了在非小细胞肺癌（NSCLC）获得性铂耐药形成后ACE2对肿瘤相关血管生成的影响。体外使用了4种NSCLC细胞系，即A549、LLC、A549-DDP和LLC-DDP，而体内使用了A549和A549-DDP细胞。A549-DDP和LLC-DDP细胞是我们机构通过将前体亲本细胞在含顺铂（CDDP）的条件培养基中培养6个月新建立的获得性铂耐药亚系。这些铂耐药细胞与其相应的亲本细胞相比，血管紧张素II 1型受体（AT1R）、ACE和VEGF的产生显著更高，而ACE2表达更低。我们发现，与相应的亲本细胞相比，ACE2过表达在体外和体内均抑制了VEGF的产生。我们还发现ACE2过表达降低了AT1R和ACE的表达。此外，我们证实ACE2过表达在人肺癌异种移植瘤中抑制细胞生长和VEGF产生，同时抑制ACE和AT1R表达。我们的研究结果表明，在获得性铂耐药形成后，ACE2过表达可能潜在地抑制NSCLC中的血管生成。
