Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas
Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas
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DOI：
10.1111/j.1349-7006.2005.00071.x
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发表时间：
2005-07-01
期刊：
影响因子：
5.7
通讯作者：
Hirohashi, S
中科院分区：
文献类型：
--
作者：
Peng, DF;Kanai, Y;Hirohashi, S
异常DNA甲基化已被证明在多种人体器官的多阶段癌变过程中发挥重要作用。本研究的目的是评估DNA甲基转移酶1 （DNMT1）蛋白表达在胰腺癌发生中的意义。我们对48例无炎症背景（DE）的外周胰管上皮、54例有炎症背景（DEI）的外周胰管上皮、188例胰腺上皮内瘤变（PanIN）和220例浸润性胰管癌的手术标本进行了DNMT1的免疫组化分析。DNMT1免疫反应性的平均发生率从DE到DEI (P = 0.003)，从DE和DEI到PanIN (P < 0.0001)，在不同发育不良级别的PanIN（从PanIN I到PanIN II， P = 0.0012），从PanIN到浸润性导管癌（P < 0.0001），以及在不同组织学分化级别的浸润性导管癌（从高分化或中度分化到低分化腺癌，P < 0.0001）中逐渐增加。浸润性导管癌中DNMT1蛋白的高水平表达与晚期t型癌（P=0.0224）和晚期癌（P=0.0294）有显著相关性。此外，DNMT1蛋白表达水平较高的浸润性导管癌患者预后较差（P = 0.0469）。这些数据表明，DNMT1蛋白表达的增加参与了从癌前阶段到导管癌恶性进展的多阶段胰腺癌的发生，并可能是不良预后的生物学预测因子。
Aberrant DNA methylation has been shown to play an important role during multistage carcinogenesis in various human organs. The aim of the present study was to evaluate the significance of DNA methyltransferase 1 (DNMT1) protein expression during pancreatic carcinogenesis. Immunohistochemical analysis of DNMT1 in 48 peripheral pancreatic duct epithelia showing no remarkable histological findings without an inflammatory background (DE), 54 peripheral pancreatic duct epithelia with an inflammatory background (DEI), 188 pancreatic intraepithelial neoplasias (PanIN), and 220 areas of invasive ductal carcinoma from surgical specimens resected from 100 patients, was carried out. The average incidence of DNMT1 immunoreactivity increased progressively from DE to DEI (P = 0.003), from DE and DEI to PanIN (P < 0.0001), among PanIN with different grades of dysplasia (from PanIN I to PanIN II, P = 0.0012), from PanIN to invasive ductal carcinomas (P < 0.0001) and among invasive ductal carcinomas with different grades of histological differentiation (from well or moderately to poorly differentiated adenocarcinomas, P < 0.0001). High-level DNMT1 protein expression in invasive ductal carcinomas was correlated significantly with an advanced t category (P=0.0224) and an advanced stage (P=0.0294). Moreover, patients with invasive ductal carcinomas showing high-level DNMT1 protein expression had a poorer outcome (P = 0.0469). These data suggest that increased DNMT1 protein expression participates in multistage pancreatic carcinogenesis from the precancerous stage to malignant progression of ductal carcinomas and may be a biological predictor of poor prognosis.