Shibahara Takuji, Onishi Takehisa, Franco Omar E, Arima Kiminobu, Nishikawa Kohei, Yanagawa Makoto, Hioki Takuichi, Watanabe Masatoshi, Hirokawa Yoshifumi, Shiraishi Taizo, Sugimura Yoshiki
Department of Urology, Mie University Faculty of Medicine, Edobashi, Tsu, Japan.
Anticancer Res. 2006 Sep-Oct;26(5A):3365-71.
Prostate-specific antigen (PSA) gene expression is regulated by androgen receptor (AR) through androgen response elements (AREs) in the promoter region of the PSA gene. A single nucleotide polymorphism with guanine (G) to adenine (A) substitution is identified at position -158 in the ARE of the PSA gene. The purpose of this study was to investigate the allelic differences in the PSA promoter activity in vitro and the relation to several clinical factors of prostate cancer patients in the Japanese population. No significant differences of promoter activity in luciferase assay and binding activity of androgen receptor were noted between the two alleles in vitro. The PSA -158 G/A polymorphism was determined by PCR amplification and restriction digestion assays in 101 organ-confined prostate cancer (PC) patients who underwent radical prostatectomy and 52 controls with benign prostatic hyperplasia. The results revealed that homozygosity for the A allele in Japanese is less common (only 8.5%) than in ethnic populations. There were no significant differences in serum PSA value at the time of diagnosis, differentiation of cancer, pathological stage, cancer volume or ratio of serum PSA/ cancer volume. However, cancer volume after neoadjuvant endocrine therapy was significantly smaller in GG genotype than in AA + AG genotypes. Our data indicate that the PSA -158 G/A polymorphism has no effect on the PSA promoter activity in vitro and no association with the serum PSA level in Japanese men, however suggest that the patients with GG genotype of ARE1 may be more sensitive to androgen ablation therapy. Taken together, the ARE1 polymorphism in the PSA gene promoter may be one of the biomarkers for response to androgen deprivation therapy.
前列腺特异性抗原（PSA）基因表达受雄激素受体（AR）通过PSA基因启动子区域的雄激素反应元件（AREs）调控。在PSA基因的ARE区域第-158位鉴定出一个鸟嘌呤（G）到腺嘌呤（A）替换的单核苷酸多态性。本研究的目的是在体外研究PSA启动子活性的等位基因差异以及与日本人群前列腺癌患者若干临床因素的关系。在体外，两个等位基因之间在荧光素酶测定中的启动子活性和雄激素受体的结合活性均未发现显著差异。通过PCR扩增和限制性消化分析对101例行根治性前列腺切除术的局限性前列腺癌（PC）患者和52例良性前列腺增生对照者进行了PSA -158 G/A多态性检测。结果显示，日本人中A等位基因的纯合子比其他种族人群少见（仅8.5%）。在诊断时的血清PSA值、癌症分化程度、病理分期、癌体积或血清PSA/癌体积比值方面均无显著差异。然而，新辅助内分泌治疗后的癌体积在GG基因型患者中显著小于AA + AG基因型患者。我们的数据表明，PSA -158 G/A多态性在体外对PSA启动子活性无影响，与日本男性的血清PSA水平无关，但提示ARE1的GG基因型患者可能对雄激素剥夺治疗更敏感。综上所述，PSA基因启动子中的ARE1多态性可能是雄激素剥夺治疗反应的生物标志物之一。
