Linja Marika J, Porkka Kati P, Kang Zhikang, Savinainen Kimmo J, Jänne Olli A, Tammela Teuvo L J, Vessella Robert L, Palvimo Jorma J, Visakorpi Tapio
Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, FIN-33014 Tampere, Finland.
Clin Cancer Res. 2004 Feb 1;10(3):1032-40. doi: 10.1158/1078-0432.ccr-0990-3.
The androgen receptor (AR)-mediated signaling pathway seems to be essentially involved in the development and progression of prostate cancer. In vitro studies have shown that altered expression of AR coregulators may significantly modify transcriptional activity of AR, suggesting that these coregulators could also contribute to the progression of prostate cancer. Here, our goal was to assess alterations in the expression of the AR coregulators in prostate cancer in vivo.
The expression of 16 AR coactivators and corepressors (SRC1, beta-catenin, TIF2, PIAS1, PIASx, ARIP4, BRCA1, AIB1, AIB3, CBP, STAT1, NCoR1, AES, cyclin D1, p300, and ARA24) was measured in prostate cancer cell lines, xenografts, and clinical prostate tumor specimens by using real-time quantitative reverse transcription-PCR. In addition, gene copy number of SRC1 was analyzed by fluorescence in situ hybridization.
Both AR-positive and AR-negative cell lines and xenografts expressed the coregulators. Most of the coregulators studied were expressed at equal levels in benign prostatic hyperplasia and untreated and hormone-refractory carcinomas. However, the expression of PIAS1 and SRC1 was significantly (P = 0.048 and 0.017, respectively) lower in hormone-refractory prostate tumors than in untreated prostate tumors. No overexpression of the coregulators was found in the clinical material. Paradoxically, the SRC1 gene was found to be amplified and highly expressed in a LuCaP 70 prostate cancer xenograft.
These findings suggest that the decreased expression of PIAS1 and SRC1 could be involved in the progression of prostate cancer. In addition, gene amplification of SRC1 in one of the xenografts implies that, in some tumors, genetic alteration of SRC1 may provide a growth advantage.
雄激素受体（AR）介导的信号通路似乎在前列腺癌的发生和发展中起关键作用。体外研究表明，AR共调节因子表达的改变可能显著改变AR的转录活性，提示这些共调节因子也可能参与前列腺癌的进展。在此，我们的目标是评估体内前列腺癌中AR共调节因子表达的改变。
通过实时定量逆转录PCR检测16种AR共激活因子和共抑制因子（SRC1、β-连环蛋白、TIF2、PIAS1、PIASx、ARIP4、BRCA1、AIB1、AIB3、CBP、STAT1、NCoR1、AES、细胞周期蛋白D1、p300和ARA24）在前列腺癌细胞系、异种移植瘤和临床前列腺肿瘤标本中的表达。此外，通过荧光原位杂交分析SRC1的基因拷贝数。
AR阳性和AR阴性细胞系及异种移植瘤均表达共调节因子。大多数研究的共调节因子在良性前列腺增生、未经治疗的和激素难治性癌中表达水平相当。然而，PIAS1和SRC1在激素难治性前列腺肿瘤中的表达显著低于未经治疗的前列腺肿瘤（P分别为0.048和0.017）。在临床材料中未发现共调节因子的过表达。矛盾的是，在一个LuCaP 70前列腺癌异种移植瘤中发现SRC1基因扩增且高表达。
这些发现提示PIAS1和SRC1表达降低可能参与前列腺癌的进展。此外，一个异种移植瘤中SRC1的基因扩增意味着，在某些肿瘤中SRC1的基因改变可能提供生长优势。
