Shamma A, Doki Y, Shiozaki H, Tsujinaka T, Inoue M, Yano M, Kimura Y, Yamamoto M, Monden M
Department of Surgery II, Osaka University, Medical School, Suita, Osaka 565, Japan.
Int J Oncol. 1998 Sep;13(3):455-60. doi: 10.3892/ijo.13.3.455.
Cyclin D1, which functionally competes with the tumor suppressor genes retinoblastoma (Rb) and p16INK4, is widely recognized as an oncogene. P27KIP1, which inhibits the cyclin D1-CDK4 complex, is also a putative tumor suppressor gene. In order to evaluate the regulatory interaction of these molecules, a retrospective series of tissues from 66 patients with esophageal squamous cell carcinoma was evaluated immunohistochemically for the expressions of cyclin D1, Rb, p16INK4 and p27KIP1. The expressions of these molecules were correlated with the proliferation cell nuclear antigen (PCNA) index as an indicator of cell proliferation. Cyclin D1 was overexpressed (++) in 28 cases (42%), Rb was lost (-) in 19 cases (24%), p16INK4 was lost (-) in 37 cases (56%) and p27KIP1 was lost (-) in 27 cases (41%). Taken together, disorder of at least one or more of these molecules was observed in 62 cases (92%). Expression of cyclin D1 and p16INK4 was negatively correlated (p<0.03), while expression of cyclin D1 and p27KIP1 was positively correlated (p<0.0004). We found strong overall correlation between expression of cyclin D1 and the PCNA index (p<0.0001), however expression of p16INK4 and p27KIP1 was significantly correlated with the PCNA index in tumors devoid of cyclin D1 overexpression (p<0.03 and p<0.02 respectively). Thus, it was found that cyclin D1 plays a major role and closely related to abnormal cell proliferation in esophageal cancer, however assessment of p16INK4 and p27KIP1 status, particularly in tumors devoid of cyclin D1 overexpression, is necessary for comprehensive evaluation of cancer cell proliferation. Furthermore, expression of cyclin D1 is correlated with that of p16INK4 and p27KIP1 in squamous cell carcinoma of the esophagus.
细胞周期蛋白D1在功能上与肿瘤抑制基因视网膜母细胞瘤（Rb）和p16INK4相互竞争，被广泛认为是一种癌基因。P27KIP1可抑制细胞周期蛋白D1-CDK4复合物，它也是一种假定的肿瘤抑制基因。为了评估这些分子之间的调控相互作用，对66例食管鳞状细胞癌患者的一系列组织进行回顾性研究，采用免疫组织化学方法检测细胞周期蛋白D1、Rb、p16INK4和p27KIP1的表达。这些分子的表达与作为细胞增殖指标的增殖细胞核抗原（PCNA）指数相关。细胞周期蛋白D1在28例（42%）中过度表达（++），Rb在19例（24%）中缺失（-），p16INK4在37例（56%）中缺失（-），p27KIP1在27例（41%）中缺失（-）。总体而言，62例（92%）中观察到这些分子中至少一种或多种出现紊乱。细胞周期蛋白D1和p16INK4的表达呈负相关（p<0.03），而细胞周期蛋白D1和p27KIP1的表达呈正相关（p<0.0004）。我们发现细胞周期蛋白D1的表达与PCNA指数之间存在很强的总体相关性（p<0.0001），然而在没有细胞周期蛋白D1过度表达的肿瘤中，p16INK4和p27KIP1的表达与PCNA指数显著相关（分别为p<0.03和p<0.02）。因此，发现细胞周期蛋白D1起主要作用且与食管癌中异常细胞增殖密切相关，然而评估p16INK4和p27KIP1的状态，特别是在没有细胞周期蛋白D1过度表达的肿瘤中，对于全面评估癌细胞增殖是必要的。此外，在食管鳞状细胞癌中，细胞周期蛋白D1的表达与p16INK4和p27KIP1的表达相关。
