Overexpression of the cyclin-dependent kinase inhibitor p16 is associated with tumor recurrence in human prostate cancer.
Overexpression of the cyclin-dependent kinase inhibitor p16 is associated with tumor recurrence in human prostate cancer.
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发表时间：
1999-05
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通讯作者：
C. T. Lee;P. Capodieci;I. Osman;M. Fazzari;J. Ferrara;H. Scher;C. Cordon-Cardo
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作者：
C. T. Lee;P. Capodieci;I. Osman;M. Fazzari;J. Ferrara;H. Scher;C. Cordon-Cardo
Ink4a基因定位于9p21区域，最初被描述为编码148个氨基酸的蛋白质，命名为p16。P16蛋白仅与CDK4和CDK6结合，抑制它们与D-型细胞周期蛋白的络合作用，从而抑制pRb的磷酸化。这有助于细胞周期停滞。本研究的目的是评估p16在一组特征明确的前列腺癌中的表达模式，同时探索p16的变化与临床病理变量之间的潜在联系。本文对88例前列腺癌患者的正常组织和恶性组织进行了检测。用原位杂交和免疫组织化学方法分别检测Ink4a外显子1α转录本的状态和p16蛋白水平。用Mantel-Haenszel CHI2检验评估表达改变与临床病理变量之间的关系，包括治疗前前列腺特异性抗原(PSA)水平、Gleason分级、病理分期和激素状况。术后生化指标(PSA)复发率采用Kaplan-Meier法和LOG-RANK检验。正常前列腺和良性增生组织中未检测到p16表达和Ink4a外显子1α转录本。然而，38例(43%)前列腺癌p16核过度表达，其余50例(57%)p16核表达阴性。P16蛋白的过度表达与Ink4a外显子1α转录本的增加有关。治疗前PSA值较高(P=0.018)、新辅助雄激素消融术(P=0.001)和前列腺癌根治术后复发时间较早(P=0.002)与p16过度表达有关。这些数据表明，p16的过度表达与前列腺癌患者的肿瘤复发和不良的临床病程有关。
The INK4A gene maps to the 9p21 region and was initially described [M. Serrano et al., Nature (Lond.), 366: 704-707, 1993; A. Kamb et al., Science (Washington DC), 264: 436-440, 1994] as encoding a 148-amino-acid protein termed p16. The p16 protein associates exclusively with Cdk4 and Cdk6, inhibiting their complexation with D-type cyclins and the consequent phosphorylation of pRb. This contributes to cell cycle arrest. The purpose of the present study was to evaluate patterns of p16 expression in a well-characterized cohort of prostatic adenocarcinomas while exploring potential associations between alterations of p16 and clinicopathological variables. Normal and malignant tissues from 88 patients with prostate carcinoma were examined. In situ hybridization and immunohistochemistry assays were used to determine the status of the INK4A exon 1alpha transcripts and levels of p16 protein, respectively. Associations between altered patterns of expression and clinicopathological variables, including pretreatment prostate-specific antigen (PSA) level, Gleason grade, pathological stage, and hormonal status, were evaluated using the Mantel-Haenszel chi2 test. Biochemical (PSA) relapse after surgery was evaluated using the Kaplan-Meier method and the log-rank test. Levels of p16 expression and INK4A exon 1alpha transcripts in normal prostate and benign hyperplastic tissues were undetectable. However, p16 nuclear overexpression was observed in 38 (43%) prostate carcinomas, whereas the remaining 50 (57%) cases showed undetectable p16 levels. Overexpression of p16 protein was found to correlate with increased INK4A exon 1alpha transcripts. Moreover, p16 overexpression was associated with a higher pretreatment PSA level (P = 0.018), the use of neoadjuvant androgen ablation (P = 0.001), and a sooner time to PSA relapse after radical prostatectomy (P = 0.002). These data suggest that p16 overexpression is associated with tumor recurrence and a poor clinical course in patients with prostate cancer.