Association between malignant progression of colorectal adenomas and DNA replication error and inhibition of apoptosis

本研究的目的是探讨结直肠腺瘤的恶性潜能与结直肠腺瘤中细胞凋亡和DNA复制错误的抑制之间的关系。我们检测了p53和bcl-2的过度表达，并分析了大肠腺瘤中二核苷酸的不稳定性，这些腺瘤表现出不同程度的异型增生和癌侵犯粘膜下层。p53的过度表达与不典型增生的进展和癌症浸润的深度有关。然而，bcl-2过表达的频率并没有根据异型增生的程度而增加。我们还研究了p21 WAF 1和PCNA在伴有不同程度异型增生的腺瘤和伴有粘膜下浸润的癌中的表达，并探讨了细胞周期的不规则性是否与大肠肿瘤的发生发展有关。在高度异型增生的腺瘤中，p21 WAF 1阳性而p53过表达阴性的腺瘤的PCNA标记指数显著低于p21 WAF 1和p53过表达均阳性的腺瘤。这些结果提示，p21 WAF 1的表达可能抑制了一些高度异型增生的腺瘤的增殖，而p53的表达与此无关。对87例肿瘤进行了遗传学分析，发现27%的肿瘤存在DNA复制错误。我们对福尔马林固定石蜡包埋的腺瘤的DNA进行了DNA复制错误分析，但这种DNA的PCR扩增效率不太好，无法进行研究。进一步的研究是必要的，以澄清在大肠癌发生的DNA复制错误的作用。

The aim of this study is to investigate the association between malignant potency of colorectal adenomas to progress to carcinoma and the inhibition of apoptosis and DNA replication errors in colorectal adenomas. We examined p53 and bcl-2 overexpression, and analyzed dinucleotide instability in colorectal adenomas showing various degree of dysplasia and carcinomas invading submucosa. Overexpression of p53 was associated with progression dysplasia and depth of cancer invasion. However, the frequency of bcl-2 overexpression was not increased according to the degree of dysplasia. We also studied p21 WAF1 and PCNA expression in adenomas with various degree of dysplasia and carcinomas with submucosal invasion, and investigated whether the irregularity of cell cycle was related to the development of colorectal tumors. In adenomas showing high grade dysplasia, the PCNA labeling index in adenomas which were positive for p21 WAF1 and negative for p53 overexpression was significantly lower than in adenomas which were both positive for p21 WAF1 and p53 overexpression. These results suggest that proliferation of some of adenomas with high grade dysplasia might be suppressed by p21 WAF1 expression which was induced irrespective of p53 expression. The analysis of genetic alterations in carcinomas showed that 27% of 87 tumors had DNA replication error. We undertook analysis of DNA replication error in DNAs from formalin-fixed paraffin-embedded adenomas, but efficiency of PCR amplification of such DNAs was not so good to perform the study. Further study is necessary to clarify the role of DNA replication error in colorectal carcinogenesis.