Targeted overexpression of vav3 oncogene in prostatic epithelium induces nonbacterial prostatitis and prostate cancer.
Targeted overexpression of vav3 oncogene in prostatic epithelium induces nonbacterial prostatitis and prostate cancer.
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DOI：
10.1158/0008-5472.can-08-0645
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发表时间：
2008-08-01
期刊：
影响因子：
11.2
通讯作者：
Lu S
中科院分区：
文献类型：
--
作者：
Liu Y;Mo JQ;Hu Q;Boivin G;Levin L;Lu S;Yang D;Dong Z;Lu S
我们先前的研究发现，Vav3癌基因在人前列腺癌中过表达，激活雄激素受体(AR)，并刺激前列腺癌细胞的生长。本研究的目的是进一步确定Vav3在基因工程小鼠前列腺癌发生发展中的潜在作用。我们通过在前列腺上皮靶向过表达具有结构性活性的Vav3获得了Vav3转基因小鼠。我们发现，Vav3的过表达导致了小鼠前列腺上皮内瘤变和前列腺癌的发展，最早在3个月大的时候。在Vav3转基因小鼠的前列腺中，AR信号轴和磷脂酰肌醇3-激酶-Akt信号增强。除了前列腺癌，Vav3转基因小鼠还出现了前列腺癌的显著非细菌性慢性前列腺炎，并伴有显著的淋巴细胞单核细胞(单核细胞、淋巴细胞和浆细胞)的渗透，这与前列腺癌的发病率升高有关。基因芯片和信号通路分析表明，Vav3转基因小鼠最常见的疾患是炎症性疾病和前列腺癌。体外分析表明，Vav3在前列腺癌细胞中的过表达增强了核因子-κB(NF-κB)的活性，这可能是Vav3活性升高所引发的先天炎症反应的一个潜在机制。这些数据表明，Vav3在前列腺上皮中的过表达增强了AR信号轴和NF-κB介导的途径，这可能是非细菌性前列腺炎和前列腺癌的发生发展的原因。
Our previous study revealed that Vav3 oncogene is overexpressed in human prostate cancer, activates androgen receptor (AR), and stimulates growth in prostate cancer cells. The purpose of this study is to further determine the potential role of Vav3 in prostate cancer development in genetically engineered mouse model. We generated Vav3 transgenic mice by targeted overexpression of a constitutive active Vav3 in the prostatic epithelium. We found that overexpression of Vav3 led to development of mouse prostatic intraepithelial neoplasia and prostate cancer at the age of as early as 3 months. The AR signaling axis and phosphatidylinositol 3-kinase-Akt signaling were elevated in the prostate glands of Vav3 transgenic mice. In addition to prostate cancer, Vav3 transgenic mice developed significant nonbacterial chronic prostatitis in the prostate gland with notable infiltration of lymphomononuclear cells (monocytes, lymphocytes, and plasma cells), which was associated with elevated incidence of prostate cancer. DNA microarray and signaling pathway analysis revealed that the top diseases and disorders were inflammatory diseases and cancer of the prostate gland in Vav3 transgenic mice. In vitro analysis showed that overexpression of Vav3 in prostate cancer cells enhanced nuclear factor-κB (NF-κB) activity, implicating an underlying mechanism of innate inflammatory response induced by elevated Vav3 activity. These data showed that Vav3 overexpression in the prostate epithelium enhanced both the AR signaling axis and NF-κB–mediated pathway, which potentially contributed to the development of nonbacterial prostatitis and prostate cancer.