Corin Irina, Di Giacomo Marilena C, Lastella Patrizia, Bagnulo Rosanna, Guanti Ginevra, Simone Cristiano
Department of Oncology, Sahlgrenska Hospital, Gothenburg University, Gothenburg, Sweden.
Cancer Biol Ther. 2006 Feb;5(2):198-203. doi: 10.4161/cbt.5.2.2356. Epub 2006 Feb 28.
Several molecules involved in cancer biology have been studied as potential prognostic markers. Recently, overexpression of cyclin E and its low-molecular-weight (LMW) isoforms has been reported to be the most prominent prognostic marker in breast cancer, surpassing proliferation index, ploidy, and axillary nodal involvement. Furthermore, cyclin E and p53 are considered the main factors controlling the euploid equilibrium in human cells. We investigated the status of cyclin E and p53 in cell lines and tissue samples of colorectal cancer, one of the leading causes of death from a tumor in the Western world.
We analyzed colorectal cancer cells, from established cell lines and patient specimens, to determine the protein levels of cyclin E and p53, and to detect p53 and APC mutations, microsatellite and chromosome instability. In addition, we assessed the presence of cyclin E LMW isoforms and their enzymatic activity.
Colorectal cancer cells expressed hyperactive LMW forms both in vitro and in vivo. These tumor-specific isoforms are correlated to genomic instability even in p53-proficient cells, and represented a constant feature in the tumors analyzed.
In colorectal cancer, the formation of cyclin E LMW forms is an early event leading to DNA-damage checkpoint-independent proliferation. Collectively, our results provide evidence that evaluation of LMW forms could represent a novel tool in the molecular characterization of colorectal tumors aimed at identifying sensitive prognostic factors and uncovering subsets of high-risk patients within the traditional categories.
几种参与癌症生物学过程的分子已被作为潜在的预后标志物进行研究。最近，有报道称细胞周期蛋白E及其低分子量（LMW）亚型的过表达是乳腺癌中最显著的预后标志物，超过了增殖指数、倍体和腋窝淋巴结受累情况。此外，细胞周期蛋白E和p53被认为是控制人类细胞整倍体平衡的主要因素。我们研究了结直肠癌（西方世界肿瘤致死的主要原因之一）细胞系和组织样本中细胞周期蛋白E和p53的状态。
我们分析了来自已建立的细胞系和患者标本的结肠癌细胞，以确定细胞周期蛋白E和p53的蛋白水平，并检测p53和APC突变、微卫星和染色体不稳定性。此外，我们评估了细胞周期蛋白E LMW亚型的存在及其酶活性。
结肠癌细胞在体外和体内均表达高活性的LMW形式。即使在p53功能正常的细胞中，这些肿瘤特异性亚型也与基因组不稳定性相关，并且在所分析的肿瘤中是一个恒定特征。
在结直肠癌中，细胞周期蛋白E LMW形式的形成是导致不依赖DNA损伤检查点的增殖的早期事件。总体而言，我们的结果提供了证据，表明对LMW形式的评估可能代表一种新工具，用于结直肠癌的分子特征分析，旨在识别敏感的预后因素并在传统分类中发现高危患者亚组。
