Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer.
Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer.
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血管紧张素 II 2 型受体促进膀胱癌细胞凋亡并抑制血管生成
DOI：
10.1186/s13046-017-0542-0
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发表时间：
2017-06-09
期刊：
影响因子：
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通讯作者：
Li H
中科院分区：
文献类型：
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作者：
Pei N;Mao Y;Wan P;Chen X;Li A;Chen H;Li J;Wan R;Zhang Y;Du H;Chen B;Jiang G;Xia M;Sumners C;Hu G;Gu D;Li H
背景：膀胱癌（BCa）是世界上第九大常见癌症。不仅需要提高诊断标记物的准确性，而且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），包括血管紧张素1型（AT1R）， 2型（AT2R）和Mas受体，在肿瘤发生中起重要作用，并可能指导我们满足这些需求。结果在本研究中，我们首次观察到BCa标本中AT1R和Mas的表达水平显著上调，而AT2R的表达水平显著下调。病毒载体介导AT2R过表达诱导体外BCa细胞凋亡，显著抑制BCa细胞增殖，提示有治疗作用。对其机制的研究表明，AT2R过表达可增加caspase-3、caspase-8和p38的表达水平，降低pErk的表达水平。PCR阵列分析显示，AT2R过表达还导致2个凋亡相关基因（BCL2A1、TNFSF25）上调，8个凋亡相关基因（casp6、casp9、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物肿瘤大小显著减小。结论AT1R、AT2R或Mas均可作为BCa的诊断标志物，AT2R是BCa基因治疗的新靶标基因。
BackgroundBladder 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.ResultsIn 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.ConclusionsTaken 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.