Pei Nana, Mao Yingying, Wan Pengfei, Chen Xinglu, Li Andrew, Chen Huiying, Li Jinlong, Wan Renqiang, Zhang Yanling, Du Hongyan, Chen Baihong, Jiang Guangyu, Xia Minghan, Sumners Colin, Hu Guixue, Gu Dongsheng, Li Hongwei
Department of Clinical Pathology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China.
School of Laboratory Medicine and Biotechnology, Southern Medical University, 1023 South Shatai Road, Guangzhou, Guangdong, 510515, China.
J Exp Clin Cancer Res. 2017 Jun 9;36(1):77. doi: 10.1186/s13046-017-0542-0.
Bladder cancer (BCa) is the ninth most common form of cancer in the world. There is a continuing need not only for improving the accuracy of diagnostic markers but also for the development of new treatment strategies. Recent studies have shown that the renin-angiotensin system (RAS), which include the angiotensin type 1 (AT1R), type 2(AT2R), and Mas receptors, play an important role in tumorigenesis and may guide us in meeting those needs.
In this study, we first observed that AT1R and Mas expression levels were significantly upregulated in BCa specimens while AT2R was significantly downregulated. Viral vector mediated overexpression of AT2R induced apoptosis and dramatically suppressed BCa cell proliferation in vitro, suggesting a therapeutic effect. Investigation into the mechanism revealed that the overexpression of AT2R increases the expression levels of caspase-3, caspase-8, and p38 and decreases the expression level of pErk. AT2R overexpression also leads to upregulation of 2 apoptosis-related genes (BCL2A1, TNFSF25) and downregulation of 8 apoptosis-related genes (CASP 6, CASP 9, DFFA, IGF1R, PYCARD, TNF, TNFRSF21, TNFSF10, NAIP) in transduced EJ cells as determined by PCR Array analysis. In vivo, we observed that AT2R overexpression caused significant reduction in xenograft tumors sizes by downregulation VEGF and induction of apoptosis.
Taken together, the data suggest that AT1R, AT2R or Mas could be used as a diagnostic marker of BCa and AT2R is a promising novel target gene for BCa gene therapy.
膀胱癌（BCa）是全球第九大常见癌症。不仅持续需要提高诊断标志物的准确性，还需要开发新的治疗策略。最近的研究表明，肾素 - 血管紧张素系统（RAS），包括1型血管紧张素受体（AT1R）、2型血管紧张素受体（AT2R）和Mas受体，在肿瘤发生中起重要作用，可能有助于满足这些需求。
在本研究中，我们首先观察到在BCa标本中AT1R和Mas的表达水平显著上调，而AT2R显著下调。病毒载体介导的AT2R过表达诱导细胞凋亡，并在体外显著抑制BCa细胞增殖，提示具有治疗作用。机制研究表明，AT2R过表达增加了caspase - 3、caspase - 8和p38的表达水平，并降低了pErk的表达水平。通过PCR Array分析确定，AT2R过表达还导致转导的EJ细胞中2个凋亡相关基因（BCL2A1、TNFSF25）上调，8个凋亡相关基因（CASP 6、CASP 9、DFFA、IGF1R、PYCARD、TNF、TNFRSF21、TNFSF10、NAIP）下调。在体内，我们观察到AT2R过表达通过下调VEGF和诱导细胞凋亡导致异种移植瘤大小显著减小。
综上所述，数据表明AT1R、AT2R或Mas可作为BCa的诊断标志物，且AT2R是BCa基因治疗中有前景的新型靶基因。
