Involvement of angiotensin II type 2 receptor (AT2R) signaling in human pancreatic ductal adenocarcinoma (PDAC): a novel AT2R agonist effectively attenuates growth of PDAC grafts in mice
Involvement of angiotensin II type 2 receptor (AT2R) signaling in human pancreatic ductal adenocarcinoma (PDAC): a novel AT2R agonist effectively attenuates growth of PDAC grafts in mice
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DOI：
10.1080/15384047.2014.1002357
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发表时间：
2015-02-01
影响因子：
3.6
通讯作者：
Tamura, Masaaki
中科院分区：
文献类型：
--
作者：
Ishiguro, Susumu;Yoshimura, Kiyoshi;Tamura, Masaaki
我们最近发现血管紧张素II型2受体（AT2R）信号在胰腺癌中的潜在参与。为了研究AT2R表达在人PDAC中的作用，我们利用手术解剖的人PDAC标本，通过免疫组织化学和实时PCR技术，评估了人PDAC和邻近正常组织中AT2R以及主要血管紧张素II受体（1型受体，AT1R）的表达。在免疫组织化学分析中，在正常胰腺和PDAC区域均检测到相对较强的AT1R表达，而在78.5%的PDAC标本和100%的胰腺正常区域检测到中度AT2R表达。PDAC区域的AT1R mRNA水平显著高于正常胰腺，但AT2R mRNA水平不显著高于正常胰腺。AT2R mRNA水平与总生存率呈负相关。在细胞培养中，用一种新型AT2R激动剂治疗可以显著减弱小鼠和人类PDAC细胞的生长，而对正常上皮细胞的细胞毒性可以忽略不计。在一项小鼠研究中，在肿瘤周围结缔组织中施用AT2R激动剂明显减弱了同基因小鼠中仅表达PAN02的AT2R小鼠PDAC移植物的生长。AT2R激动剂主要诱导肿瘤细胞凋亡，而不诱导基质细胞凋亡。综上所述，我们的研究结果为AT2R信号参与PDAC的发展提供了临床和临床前证据，并指出新型AT2R激动剂可以作为PDAC治疗的有效药物。
We have recently discovered the potential involvement of angiotensin II type 2 receptor (AT2R) signaling in pancreatic cancer using AT2R deficient mice. To examine the involvement of AT2R expression in human PDAC, expressions of AT2R as well as the major angiotensin II receptor (type 1 receptor, AT1R) in human PDAC and adjacent normal tissue was evaluated by immunohistochemistry and real time PCR using surgically dissected human PDAC specimens. In immunohistochemical analysis, relatively strong AT1R expression was detected consistently in both normal pancreas and PDAC areas, whereas moderate AT2R expression was detected in 78.5% of PDAC specimens and 100% of normal area of the pancreas. AT1R, but not AT2R, mRNA levels were significantly higher in the PDAC area than in the normal pancreas. AT2R mRNA levels showed a negative correlation trend with overall survival. In cell cultures, treatment with a novel AT2R agonist significantly attenuated both murine and human PDAC cell growth with negligible cytotoxicity in normal epithelial cells. In a mouse study, administrations of the AT2R agonist in tumor surrounding connective tissue markedly attenuated growth of only AT2R expressing PAN02 murine PDAC grafts in syngeneic mice. The AT2R agonist treatment induced apoptosis primarily in tumor cells but not in stromal cells. Taken together, our findings offer clinical and preclinical evidence for the involvement of AT2R signaling in PDAC development and pinpoint that the novel AT2R agonist could serve as an effective therapeutic for PDAC treatment.