Nuclear translocation of ADAM-10 contributes to the pathogenesis and progression of human prostate cancer
Nuclear translocation of ADAM-10 contributes to the pathogenesis and progression of human prostate cancer
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DOI：
10.1111/j.1349-7006.2007.00601.x
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发表时间：
2007-11-01
期刊：
影响因子：
5.7
通讯作者：
Nakagawa, Masayuki
中科院分区：
文献类型：
--
作者：
Arima, Takashi;Enokida, Hideki;Nakagawa, Masayuki
去整合素和金属蛋白酶（ADAM）是细胞膜锚定蛋白，通过细胞黏附和蛋白酶活性对人类癌细胞的转移具有潜在影响。在前列腺癌（PC）中，ADAM - 10蛋白呈现核定位，而在良性前列腺增生（BPH）中，它主要结合在细胞膜上。我们假设前列腺癌的发病机制和进展归因于ADAM - 10的核转位。免疫印迹显示，在5α - 二氢睾酮处理后，人雄激素依赖性前列腺癌细胞的核组分中一种60 kDa的ADAM - 10活性形式增加，而在细胞膜和细胞质组分中减少。免疫细胞化学显示，在5α - 二氢睾酮处理后，ADAM - 10蛋白从细胞膜转位到细胞核。在核组分中检测到雄激素受体和ADAM - 10的共免疫沉淀，但在细胞膜和细胞质组分中未检测到。对64例前列腺癌和20例良性前列腺增生样本的免疫组织化学研究表明，前列腺癌细胞核中ADAM - 10染色强度显著高于良性前列腺增生细胞核（P < 0.0001）。前列腺癌细胞膜中的染色强度也显著低于良性前列腺增生细胞膜（P = 0.0017）。核染色强度与临床T分期（P = 0.004）、格里森评分（P < 0.0001）和术前前列腺特异性抗原水平（P = 0.0061）显著相关。与对照组相比，ADAM - 10小干扰RNA转染细胞的细胞生长显著降低。我们的研究结果表明，在人类前列腺癌中，ADAM - 10与雄激素受体结合的核转位参与肿瘤生长和进展。
A disintegrin and metalloproteases (ADAM) are cell membrane-anchored proteins with potential implications for the metastasis of human cancer cells via cell adhesion and protease activities. In prostate cancer (PC), the ADAM-10 protein showed a nuclear localization whereas in benign prostate hypertrophy (BPH) it was predominantly bound to the cell membrane. We hypothesized that the pathogenesis and progression of PC are attributable to the nuclear translocation of ADAM-10. Immunoblotting revealed that after 5 alpha-dihydrotestosterone treatment, a 60-kDa active form of ADAM-10 was increased in the nuclear fraction but decreased in the cell membrane and cytoplasmic fractions of human androgen-dependent PC cells. Immunocytochemistry revealed that after 5 alpha-dihydrotestosterone treatment, the ADAM-10 protein was translocated from the cell membrane to the nucleus. Coimmunoprecipitation of androgen receptor and ADAM-10 was detected in the nuclear fraction but not in the cell membrane and cytoplasmic fractions. Immunohistochemical study of 64 PC and 20 BPH samples showed that the intensity of ADAM-10 staining was significantly higher in the nuclei of PC cells than in the nuclei of BPH cells (P < 0.0001). It was also significantly lower in the cell membrane of PC cells than in the cell membrane of BPH cells (P = 0.0017). Nuclear staining intensity was significantly correlated with the clinical T-factor (P = 0.004), the Gleason score (P < 0.0001) and preoperative prostate-specific antigen levels (P = 0.0061). ADAM-10 small interfering RNA transfectants showed a significant decrease in cell growth compared to the controls. Our results suggest that in human PC, the nuclear translocation of ADAM-10 coupled with the androgen receptor is involved in tumor growth and progression.