Sutter Thomas, Dansranjavin Temuujin, Lubinski Jan, Debniak Tadeusz, Giannakudis Joannis, Hoang-Vu Cuong, Dralle Henning
Department of General Surgery, Martin Luther University of Halle-Wittenberg, 06097 Halle, Germany.
Int J Colorectal Dis. 2002 Nov;17(6):374-80. doi: 10.1007/s00384-002-0390-y. Epub 2002 Mar 8.
A subset of colorectal carcinomas are due to a deficiency in the DNA mismatch repair system. The molecular mechanisms of tumorigenesis in these tumors is not yet well understood. Deregulation of the cell cycle, specifically of the G(1) and S phases, is a hallmark of human cancers. Transition from the G(1) to the S phase is accelerated by increased cyclin E protein expression, and recent studies suggest that overexpression of cyclin E leads to chromosomal instability. The overexpression of cyclin E in a variety of human cancers, for example in colorectal, gastric, lung, breast, and kidney cancer, provides evidence that cyclin E plays a pivotal role in the cell cycle and replication. We examined whether the overexpression of cyclin E is related to the status of the mismatch repair system in colorectal carcinomas.
Frozen tumor samples and adjacent normal colon mucosa obtained from 100 patients were subjected to microsatellite analysis, RT-PCR, western blot analysis and immunohistochemistry.
High microsatellite instability was detected in 13 tumors, and in 10 of these (77%) cyclin E protein was overexpressed at least twofold compared to normal mucosa. In contrast, only 28 of the remaining 87 microsatellite stable tumors (32%) overexpressed cyclin E. Lower molecular weight cyclin E proteins were present in 7 of 87 microsatellite stable carcinoma (8%), compared to 7 cases exhibiting lower molecular weight isoforms of 13 MSI carcinoma (54%).
Increased cyclin E protein expression and the appearance of lower molecular weight cyclin E proteins were significantly associated with MSI in colorectal tumors. The data indicate that increased and/or aberrant expression of cyclin E protein might contribute to the mutator phenotype of colorectal cancer.
一部分结直肠癌是由DNA错配修复系统缺陷所致。这些肿瘤发生的分子机制尚未完全明确。细胞周期失调，尤其是G(1)期和S期失调，是人类癌症的一个标志。细胞周期蛋白E（cyclin E）蛋白表达增加会加速从G(1)期到S期的转变，最近的研究表明cyclin E过表达会导致染色体不稳定。cyclin E在多种人类癌症中过表达，例如在结直肠癌、胃癌、肺癌、乳腺癌和肾癌中，这证明cyclin E在细胞周期和复制中起关键作用。我们研究了cyclin E过表达是否与结直肠癌中错配修复系统的状态相关。
从100例患者获取的冷冻肿瘤样本及相邻正常结肠黏膜进行微卫星分析、逆转录聚合酶链反应（RT-PCR）、蛋白质免疫印迹分析和免疫组织化学检测。
在13个肿瘤中检测到高微卫星不稳定性，其中10个（77%）肿瘤中cyclin E蛋白表达相较于正常黏膜至少过表达两倍。相比之下，其余87个微卫星稳定肿瘤中只有28个（32%）过表达cyclin E。87个微卫星稳定癌中有7个（8%）存在低分子量cyclin E蛋白，而13个微卫星高度不稳定癌中有7个（54%）出现低分子量异构体。
结直肠癌中cyclin E蛋白表达增加及低分子量cyclin E蛋白的出现与微卫星高度不稳定显著相关。数据表明cyclin E蛋白表达增加和/或异常表达可能促成结直肠癌的突变体表型。
