Loss of cell cycle regulators p27(Kip1) and cyclin E in transitional cell carcinoma of the bladder correlates with tumor grade and patient survival.
Loss of cell cycle regulators p27(Kip1) and cyclin E in transitional cell carcinoma of the bladder correlates with tumor grade and patient survival.
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DOI：
10.1097/00005392-199904010-00470
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发表时间：
1999-04
期刊：
影响因子：
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通讯作者：
J. J. Pizzo-J.;A. Borkowski;S. Jacobs;N. Kyprianou
中科院分区：
文献类型：
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作者：
J. J. Pizzo-J.;A. Borkowski;S. Jacobs;N. Kyprianou
细胞周期蛋白依赖性激酶抑制剂p27（Kip 1）是细胞周期进程的一个强大的分子决定因素。p27（Kip 1）表达缺失已被证明是几种人类恶性肿瘤疾病进展的预测指标。在这项研究中，我们研究了两个关键的细胞周期调节因子，p27（Kip 1）和细胞周期蛋白E的表达，在膀胱移行细胞癌的进展。对50例膀胱肿瘤标本（包括3例转移性淋巴结和7例正常膀胱标本）进行免疫组化分析，使用针对细胞周期两种调节因子p27（Kip 1）和cyclin E的特异性抗体。免疫反应性的程度与病理肿瘤分级、分期和患者生存期相关。在正常膀胱组织的上皮细胞中观察到p27（Kip 1）和细胞周期蛋白E的均匀强烈的免疫反应。膀胱癌组织中p27（Kip 1）和cyclin E的表达与正常膀胱组织相比有显著性差异（P < 0.01）。此外，随着肿瘤分级和病理分期的增加，两种细胞周期蛋白的表达逐渐丧失。与高分化和中等分化（I级和II级）肿瘤相比，低分化肿瘤（III级）中p27（Kip 1）的表达显著降低（P = 0.004）。此外，与I级和II级病变相比，III级肿瘤中细胞周期蛋白E的表达较低，尽管这种差异未能达到统计学显著性。最重要的是，患者生存的Kaplan-Meier曲线显示死亡风险增加与p27（Kip 1）（P = 0.001）和细胞周期蛋白E（P = 0.002）表达水平低相关。这是第一个证据表明，p27（Kip 1）和细胞周期蛋白E在人膀胱移行细胞癌细胞中的表达缺失与组织学侵袭性和患者生存率低相关。这些结果具有临床重要性，因为它们支持p27（Kip 1）和细胞周期蛋白E作为膀胱肿瘤生物学潜力的新型预测标志物的作用，这将使那些最有可能进展为肌肉浸润性疾病和患者生存的肿瘤的鉴定成为可能。
The cyclin-dependent kinase inhibitor p27(Kip1) is a powerful molecular determinant of cell cycle progression. Loss of expression of p27(Kip1) has been shown to be predictive of disease progression in several human malignancies. In this study we investigated the expression of two key cell cycle regulators, p27(Kip1) and cyclin E, in the progression of transitional cell carcinoma of the bladder. An immunohistochemical analysis was conducted in a series of 50 bladder tumor specimens, including 3 metastatic lymph nodes, and 7 normal bladder specimens, using specific antibodies against the two regulators of the cell cycle, p27(Kip1) and cyclin E. The degree of immunoreactivity was correlated with the pathological tumor grade, stage, and patient survival. A uniformly intense immunoreactivity for p27(Kip1) and cyclin E was observed in epithelial cells of normal bladder tissue. Malignant bladder tissue demonstrated a heterogeneous pattern of significantly reduced p27(Kip1) and cyclin E immunoreactivity, compared with normal urothelium (P < 0.01). In addition, there was progressive loss of expression of both cell cycle proteins with increasing tumor grade and pathological stage. Expression of p27(Kip1) was significantly lower in the poorly differentiated tumors (grades III) compared to well and moderately differentiated (grades I and II) tumors (P = 0.004). Moreover, the expression of cyclin E was lower in grade III tumors compared to grade I and II lesions, although this difference failed to reach statistical significance. Most significantly, Kaplan-Meier plots of patient survival show increased mortality risk associated with low levels of p27(Kip1) (P = 0.001) and cyclin E (P = 0.002) expression. This is the first evidence that loss of expression of p27(Kip1) and cyclin E in human bladder transitional cell carcinoma cells correlates with advancing histological aggressiveness and poor patient survival. These results have clinical importance, because they support a role for p27(Kip1) and cyclin E as novel predictive markers of the biological potential of bladder tumors that will enable identification of those tumors most likely to progress to muscle invasive disease and of patient survival.