Promotion of bladder cancer development and progression by androgen receptor signals
Promotion of bladder cancer development and progression by androgen receptor signals
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DOI：
10.1093/jnci/djk113
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发表时间：
2007-04-04
期刊：
影响因子：
--
通讯作者：
Chang, Chawnshang
中科院分区：
文献类型：
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作者：
Miyamoto, Hiroshi;Yang, Zhiming;Chang, Chawnshang
男性膀胱癌的发病率高于女性，但原因尚不清楚。与前列腺癌不同，人类膀胱癌通常不被认为依赖于激素活性。我们调查了可能参与的雄激素和雄激素受体（AR）在膀胱cancer.Methods我们使用N-丁基-N-（4-羟丁基）亚硝胺（BBN）诱导膀胱癌的野生型雄性和雌性小鼠，有和没有阉割的男性，和AR基因敲除（ARKO）的雄性和雌性小鼠，有和没有双氢睾酮（DHT）补充的男性。我们还用雄激素剥夺疗法治疗了人膀胱癌细胞系，包括TCC-BMP 3和UMUC 3，以及从这些细胞系建立的小鼠异种移植模型（抗雄激素治疗或去势），AR-小干扰RNA（AR-siRNA），或抗AR分子ASC-J 9，结果用BBN处理的野生型雄性小鼠和野生型雌性小鼠中超过92%和42%最终发展成膀胱癌，而雄性或雌性ARKO小鼠都没有。BBN治疗在25%补充有DHT的ARKO小鼠和50%去势野生型雄性小鼠中诱导膀胱癌。雄激素剥夺AR阳性的人膀胱癌细胞的雄激素耗竭在体外或去势小鼠和/或治疗与抗雄激素fluorescent在体外或体内，以及AR敲低AR-siRNA或ASC-J 9，抑制细胞增殖在体外和异种移植肿瘤生长在vivo.Conclusions我们的研究结果牵连的参与，雄激素和AR在膀胱癌。靶向AR和雄激素可能为膀胱癌提供新的化学预防和治疗方法。
Background Males have a higher incidence of bladder cancer than females, but the reason remains unknown. Unlike prostate cancer, human bladder cancer is not generally considered to be dependent on hormone activity. We investigated the possible involvement of androgens and the androgen receptor (AR) in bladder cancer.Methods We used N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) to induce bladder cancer in wild-type male and female mice, with and without castration in males, and in AR knockout (ARKO) male and female mice, with and without dihydrotestosterone (DHT) supplementation in males. We also treated human bladder cancer cell lines, including TCC-SUP and UMUC3, and mouse xenograft models established from these same lines with androgen deprivation therapy (antiandrogen treatment or castration), AR-small-interfering RNA (AR-siRNA), or the anti-AR molecule ASC-J9, which causes selective degradation of the AR.Results More than 92% of wild-type male and 42% of wild-type female mice treated with BBN eventually developed bladder cancer, whereas none of the male or female ARKO mice did. Treatment with BBN induced bladder cancer in 25% of ARKO mice supplemented with DHT and in 50% of castrated wild-type male mice. Androgen deprivation of AR-positive human bladder cancer cells by androgen depletion in vitro or castration in mice and/or by treatment with the antiandrogen flutamide in vitro or in vivo, as well as AR knockdown by AR-siRNA or by ASC-J9, suppressed cell proliferation in vitro and xenograft tumor growth in vivo.Conclusions Our findings implicate the involvement of both androgens and the AR in bladder cancer. Targeting AR and androgens may provide novel chemopreventive and therapeutic approaches for bladder cancer.