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癌(SCC)和尿路移行细胞癌(TCC)组织中细胞周期蛋白A、细胞周期蛋白B1、细胞周期蛋白D1和细胞周期蛋白E、细胞周期蛋白依赖性激酶(CDK)和p27蛋白的表达。目的：确定它们对肿瘤行为和患者预后的意义。在进展期食管鳞癌中，Cyclin A、B1或D1的阳性率高于其他类型的食管鳞癌。在膀胱移行细胞癌中，进展期肿瘤中细胞周期蛋白A或E的表达高于其他类型的肿瘤。那些过度表达这些细胞周期蛋白的患者比那些不表达这些细胞周期蛋白的患者预后要差得多。有趣的是，我们的发现还表明，在食管鳞癌中，细胞周期蛋白D1和细胞周期蛋白E以及它们的功能伙伴CDK4和CDK2在许多情况下经常表现出异常的过表达。我们还研究了免疫组织化学检测的p27表达与临床病理…的关系。鳞状细胞癌的危险因素较多。与支持p27抑瘤功能的证据相反，本研究提示p27的表达可能与鳞癌的进展有关。错配修复所支持的维持遗传稳定性在避免癌症方面发挥着重要作用。我们用免疫组织化学方法研究了hMSH2在膀胱移行细胞癌中的表达，证实hMSH2在肿瘤细胞中的表达降低与膀胱移行细胞癌的复发有关。此外，我们还通过聚合酶链式反应和直接测序分析检测了膀胱移行细胞癌基因组DNA中hMSH6基因的突变情况。P53基因的突变状态也是hMSH6功能障碍继发遗传不稳定的潜在靶点。共有3例出现hMSH6突变。22例检测到P53基因突变。P53基因突变的肿瘤均未发现hMSH6错义突变。与没有hMSH6改变的患者相比，三名hMSH6改变的患者有更多的额外原发癌症。这些发现为散发性尿路上皮癌中hMSH6突变的类型和可能涉及的频率提供了第一个活体证据。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。较少

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