Tumor-associated gene expression and DNA mismatch repair abnormality in human malignancy

应用免疫组织化学方法检测了食管鳞状细胞癌（SCC）和尿路移行细胞癌（TCC）中细胞周期蛋白A、B1、D1和E、细胞周期蛋白依赖性激酶（CDK）和p27蛋白的表达。以确定它们对肿瘤行为和患者预后的意义。在食管鳞癌中，进展性肿瘤中表现出cyclin A、B1或D1的病例的患病率高于其他类型的肿瘤。在TCC病例中，细胞周期蛋白A或E在进展性肿瘤中高于其他类型的肿瘤。SCC过度表达这些细胞周期蛋白过度表达的患者比不表达这些细胞周期蛋白的患者预后明显较差。有趣的是，我们的研究结果还表明，在食管鳞状细胞癌中，细胞周期蛋白D1和细胞周期蛋白E及其功能伙伴，CDK4和CDK2，往往表现出失调的过度表达在许多情况下。我们还研究了p27表达与临床病理特征之间的关系。 关于我们 SCC中的生理因素与支持p27肿瘤抑制功能的证据相反，本研究表明p27的表达可能与SCC的进展有关。错配修复支持的遗传稳定性的维持在避免癌症方面发挥着重要作用。我们通过免疫组化研究了hMSH2在膀胱TCC中的表达，并证明肿瘤细胞中hMSH2表达的降低与TCC的复发相关。此外，我们还通过聚合酶链反应和直接测序分析检测了TCC的基因组DNA中hMSH6基因的突变。p53基因的突变状态也被研究为继发于hMSH6功能障碍的遗传不稳定性的潜在靶点。共有3例hMSH6突变。p53基因突变22例。p53突变的肿瘤中没有hMSH6错义突变。与无hMSH6突变的病例相比，3例hMSH6突变的患者有更频繁的额外原发癌。这些发现提供了第一个在体内的证据，在散发型尿路上皮细胞癌的hMSH6突变的可能参与的改变类型和频率。我们接下来将尝试确定hMLH1启动子甲基化或突变在尿路上皮癌发生中的作用。少

We immunohistochemically examined the expression of cyclin A, B1, D1 and E, cyclin dependent kinase (CDK), and p27 proteins in esophageal squamous cell carcinoma (SCC) and transitional cell carcinoma (TCC) of the urinary tract. to determine their significance for the tumor behavior and patient prognosis. The prevalence of cases exhibiting cyclin A, B1 or D1 were higher in the progressive tumors than in the other types of tumors in esophageal SCCs. In TCC cases, cyclin A or E were higher in the progressive tumors than in the other types of tumors. Patients whose SCCs overexpressed these cyclin-overexpresion had a significantly poorer prognosis than those expressing neither of these cyclins. Interestingly, our findings also suggest that in esophageal SCC, cyclin D1 and cyclin E and their functional partners, CDK4 and CDK2, often exhibit dysregulated overexpression in many cases. We also examined the relationships between immunohistochemically-detected expression of p27 and clinicopatholo … More gical factors in SCC. In contrast to the evidence supporting a tumor-suppressive function of p27, the present study suggests that expression of p27 may be associated with the progression of SCC.Maintenance of genetic stability supported by mismatch repair plays ah important role in the avoidance of cancer. We studied hMSH2 expression in bladder TCCs by immunohistochemistry and demonstrated that reduced hMSH2 expression in tumor cells is associated with recurrence of TCCs. In addition, We examined genomic DNA from TCCs for mutations in hMSH6 gene by polymerase chain reaction and direct sequencing analysis. mutational status of p53 gene was also studied as a potential target of genetic instability secondary to hMSH6 dysfunction. A total of 3 cases displayed hMSH6 mutations. p53 gene mutations were detected in 22 cases. No tumors with p53 mutation had any hMSH6 missense mutations. Compared to the cases without hMSH6 alterations, the three patients with hMSH6 alterations ,had more frequent additional primary cancer. These findings provide the first in vivo evidence ,for the type of alterations and frequency of possible involvement of the hMSH6 mutations in sporadic type urothelial TCCs. We will next try to determine the involvement of hMLH1 promoter methylation or mutation in urothelial carcinogenesis. Less