Niehans G A, Kratzke R A, Froberg M K, Aeppli D M, Nguyen P L, Geradts J
Department of Pathology, Minneapolis Department of Veterans Affairs Medical Center, University of Minnesota Medical School, 55417, USA.
Br J Cancer. 1999 Jun;80(8):1175-84. doi: 10.1038/sj.bjc.6990483.
The G1 cell cycle checkpoint regulates entry into S phase for normal cells. Components of the G1 checkpoint, including retinoblastoma (Rb) protein, cyclin D1 and p16INK4a, are commonly altered in human malignancies, abrogating cell cycle control. Using immunohistochemistry, we examined 79 invasive transitional cell carcinomas of the urinary bladder treated by cystectomy, for loss of Rb or p16INK4a protein and for cyclin D1 overexpression. As p53 is also involved in cell cycle control, its expression was studied as well. Rb protein loss occurred in 23/79 cases (29%); it was inversely correlated with loss of p16INK4a, which occurred in 15/79 cases (19%). One biphenotypic case, with Rb+p16- and Rb-p16+ areas, was identified as well. Cyclin D1 was overexpressed in 21/79 carcinomas (27%), all of which retained Rb protein. Fifty of 79 tumours (63%) showed aberrant accumulation of p53 protein; p53 staining did not correlate with Rb, p16INK4a, or cyclin D1 status. Overall, 70% of bladder carcinomas showed abnormalities in one or more of the intrinsic proteins of the G1 checkpoint (Rb, p16INK4a and cyclin D1). Only 15% of all bladder carcinomas (12/79) showed a normal phenotype for all four proteins. In a multivariate survival analysis, cyclin D1 overexpression was linked to less aggressive disease and relatively favourable outcome. In our series, Rb, p16INK4a and p53 status did not reach statistical significance as prognostic factors. In conclusion, G1 restriction point defects can be identified in the majority of bladder carcinomas. Our findings support the hypothesis that cyclin D1 and p16INK4a can cooperate to dysregulate the cell cycle, but that loss of Rb protein abolishes the G1 checkpoint completely, removing any selective advantage for cells that alter additional cell cycle proteins.
G1期细胞周期检查点调节正常细胞进入S期。G1检查点的组成部分，包括视网膜母细胞瘤（Rb）蛋白、细胞周期蛋白D1和p16INK4a，在人类恶性肿瘤中通常会发生改变，从而废除细胞周期控制。我们采用免疫组织化学方法，检查了79例接受膀胱切除术治疗的浸润性膀胱移行细胞癌，检测Rb或p16INK4a蛋白缺失以及细胞周期蛋白D1过表达情况。由于p53也参与细胞周期控制，因此也对其表达进行了研究。23/79例（29%）出现Rb蛋白缺失；它与p16INK4a缺失呈负相关，p16INK4a缺失发生在15/79例（19%）中。还发现1例双表型病例，存在Rb+p16-和Rb-p16+区域。21/79例癌（27%）中细胞周期蛋白D1过表达，所有这些病例均保留Rb蛋白。79例肿瘤中有50例（63%）显示p53蛋白异常积聚；p53染色与Rb、p16INK4a或细胞周期蛋白D1状态无关。总体而言，70%的膀胱癌在G1检查点的一种或多种内在蛋白（Rb、p16INK4a和细胞周期蛋白D1）中存在异常。所有四种蛋白均表现正常表型的膀胱癌仅占全部膀胱癌的15%（12/79）。在多变量生存分析中，细胞周期蛋白D1过表达与侵袭性较低的疾病和相对较好的预后相关。在我们的研究系列中，Rb、p16INK4a和p53状态作为预后因素未达到统计学意义。总之，在大多数膀胱癌中可发现G1限制点缺陷。我们的研究结果支持以下假设：细胞周期蛋白D1和p16INK4a可协同作用使细胞周期失调，但Rb蛋白缺失会完全废除G1检查点，消除改变其他细胞周期蛋白的细胞的任何选择优势。
