The oncogenic potential of a prostate cancer-derived androgen receptor mutant
The oncogenic potential of a prostate cancer-derived androgen receptor mutant
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DOI：
10.1002/pros.20544
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发表时间：
2007-05-01
期刊：
影响因子：
2.8
通讯作者：
White, Ralph W. deVere
中科院分区：
文献类型：
--
作者：
Shi, Xu-Bao;Xue, Lingru;White, Ralph W. deVere
背景。雄激素受体（AR）突变在前列腺癌（CaP）发生中的作用仍不清楚。本研究的目的是评估 AR 突变对前列腺肿瘤发生的影响并确定由此产生的分子改变。方法。将野生型 AR(AR(WT)) 或 CaP 衍生的 K580RAR(AR(K580R)) 突变体稳定转染到 SV40 永生化人前列腺上皮 pRNS-1-1 细胞中，该细胞缺乏 AR 表达，无法在裸鼠中生长。在体外和体内研究了这些 AR 转染细胞系形成肿瘤的能力。此外，还对这些细胞系进行了基因表达谱分析。结果。与 AR(WT) 相比，AR(K580R) 诱导软琼脂中集落形成增加六倍以上。体内研究证实AR(K580R)转染的pRNS-1-1细胞能够在裸鼠体内形成肿瘤。结合微阵列和 RT-PCR，在 AR(K580R) 细胞中鉴定出 29 个差异表达基因。研究发现，沉默 AR(K580R) 细胞中上调的胎盘碱性磷酸酶 (ALPP) 的表达会导致细胞生长的显着抑制。此外，AR(K58OR)转染的pRNS-1-1细胞表达显着增加的p-Akt和p-p70 S6K。结论。 AR(K580R)突变促进前列腺上皮细胞恶性转化。这与 ALPP 的上调和随后 Akt 信号通路的激活有关。
BACKGROUND. The role of androgen receptor (AR) mutations in the initiation of prostate cancer (CaP) remains unclear. The purpose of this study was to assess the influence of an AR mutation on prostate tumorigenesis and to determine the resulting molecular alterations.METHODS. Wild-type AR(AR(WT)) or the CaP-derived K580RAR(AR(K580R)) mutant was stably transfected into SV40-immortalized human prostate epithelial pRNS-1-1 cells that lack AR expression and fail to grow in nude mice. The ability of these AR-transfected cell lines to form tumor was investigated in vitro and in vivo. Additionally, gene expression profiling of these cell lines was performed. RESULTS. Compared with the AR(WT), the AR(K580R) induced greater than sixfold increase in colony formation in soft agar. In vivo studies confirmed that the AR(K580R) transfected pRNS-1-1 cells were able to form tumors in nude mice. Using a combination of microarray and RT-PCR, 29 differentially expressed genes were identified in AR(K580R) cells. It was found that silencing the expression of placental alkaline phosphatase (ALPP) that was upregulated in AR(K580R) cells resulted in significant inhibition of cell growth. Furthermore, the AR(K58OR)-transfected pRNS-1-1 cells expressed markedly increased p-Akt and p-p70 S6K.CONCLUSION. The AR(K580R) mutation promoted the malignant transformation of prostate epithelial cells. This was associated with upregulation of ALPP and subsequent activation of the Akt signaling pathway.