Yin Lei, Mao Lixin, Yin Rui, Lv Chengxun, Shi Xiaokai, Yue Chuang, Chen Yin, Lu Chao, Wu Zonglin, Xu Kai, Cao Wei
Department of Urology, Shidong Hospital, Yangpu District, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, 200438, People's Republic of China.
Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
Biologics. 2024 Dec 19;18:397-412. doi: 10.2147/BTT.S485178. eCollection 2024.
Emerging literature links the role of the renin-angiotensin-aldosterone system (RAAS) to the progression of cancers. However, the function of RAAS has not been verified in Clear-cell renal cell carcinoma (ccRCC).
ACE expression in ccRCC tissues was determined using RT-PCR, Western blot, and immunohistochemistry staining. The clinical significance of ACE was evaluated through Cox regression analysis. To assess the impact of ACE expression on ccRCC cell growth, metastasis, and glucose activity, CCK-8 assays, transwell assays, Seahorse detection, and xenograft models were utilized. The mechanisms of ACE and its upstream and downstream regulatory factors were investigated using RNA-seq, chromatin immunoprecipitation (ChIP), and luciferase reporter assays.
RAAS-related gene Angiotensin-Converting Enzyme (ACE) was significantly under expressed in ccRCC cells and tissues. High ACE expression was positively associated with a favorable prognosis in ccRCC patients. Functional studies showed that ACE overexpression suppressed ccRCC cell line OS-RC-2 and A498 growth, metastasis, and glycolysis activities, while its knockdown had the opposite effect. Mechanistically, ACE inhibited ccRCC progression and epithelial-mesenchymal transition (EMT) by disrupting the AKT-FOXO1 signaling pathway. Furthermore, we provide evidence that ACE could enhance everolimus (approved agent for ccRCC) antitumor effect and ACE expression is transcriptionally regulated by ZBTB26.
Our findings investigated the roles and mechanisms of ACE in ccRCC. ACE inhibits the growth and metastasis of ccRCC cells in vitro and in vivo by promoting FOXO1 expression, which is the downstream target of PI3K-AKT pathway. Thus, this research suggests that ACE may be a promising target for new therapeutic strategy in ccRCC.
新出现的文献将肾素-血管紧张素-醛固酮系统（RAAS）的作用与癌症进展联系起来。然而，RAAS的功能在透明细胞肾细胞癌（ccRCC）中尚未得到证实。
采用逆转录-聚合酶链反应（RT-PCR）、蛋白质免疫印迹法和免疫组织化学染色法检测ccRCC组织中血管紧张素转换酶（ACE）的表达。通过Cox回归分析评估ACE的临床意义。为了评估ACE表达对ccRCC细胞生长、转移和糖代谢活性的影响，采用细胞计数试剂盒-8（CCK-8）检测法、Transwell检测法、海马体检测法和异种移植模型。利用RNA测序（RNA-seq）、染色质免疫沉淀（ChIP）和荧光素酶报告基因检测法研究ACE及其上下游调节因子的机制。
RAAS相关基因血管紧张素转换酶（ACE）在ccRCC细胞和组织中显著低表达。ACE高表达与ccRCC患者的良好预后呈正相关。功能研究表明，ACE过表达抑制ccRCC细胞系OS-RC-2和A498生长、转移及糖酵解活性，而其敲低则产生相反作用。机制上，ACE通过破坏AKT-FOXO1信号通路抑制ccRCC进展和上皮-间质转化（EMT）。此外，我们提供证据表明ACE可增强依维莫司（ccRCC的获批药物）的抗肿瘤作用，且ACE表达受锌指蛋白26（ZBTB26）转录调控。
我们的研究结果探讨了ACE在ccRCC中的作用和机制。ACE通过促进PI3K-AKT通路的下游靶点FOXO1表达，在体外和体内抑制ccRCC细胞的生长和转移。因此，本研究提示ACE可能是ccRCC新治疗策略的一个有前景的靶点。
