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

我们用免疫组织化学方法检测了细胞周期蛋白A、B1、D1和E、细胞周期蛋白依赖激酶（CDK）和p27蛋白在食管鳞状细胞癌（SCC）和尿路移行细胞癌（TCC）中的表达。探讨其对肿瘤行为及患者预后的意义。食管鳞状细胞癌进展性肿瘤中出现周期蛋白A、B1或D1的比例高于其他类型肿瘤。在TCC病例中，进展性肿瘤中的细胞周期蛋白A或E高于其他类型的肿瘤。SCCs过表达这些细胞周期蛋白的患者的预后明显比不表达这两种细胞周期蛋白的患者差。有趣的是，我们的研究结果还表明，在食管SCC中，cyclin D1和cyclin E及其功能伙伴CDK4和CDK2在许多情况下经常表现出失调的过表达。我们还研究了免疫组织化学检测的p27表达与SCC临床病理因素之间的关系。与支持p27的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中起着重要作用。我们通过免疫组化研究了hMSH2在膀胱tcc中的表达，发现肿瘤细胞中hMSH2表达的降低与tcc的复发有关。此外，我们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hMSH6功能障碍继发遗传不稳定的潜在靶点。hMSH6基因突变3例。22例检测到P53基因突变。p53突变的肿瘤无hMSH6错义突变。与没有hMSH6改变的病例相比，三名hMSH6改变的患者有更频繁的额外原发性癌症。这些发现提供了第一个体内证据，证明了散在型尿路上皮tcc中hMSH6突变的改变类型和可能涉及的频率。接下来，我们将尝试确定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