Hypermethylation-mediated reduction of WWOX expression in intraductal papillary mucinous neoplasms of the pancreas
Hypermethylation-mediated reduction of WWOX expression in intraductal papillary mucinous neoplasms of the pancreas
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DOI：
10.1038/sj.bjc.6604986
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发表时间：
2009-04-28
影响因子：
8.8
通讯作者：
Yokozaki, H.
中科院分区：
文献类型：
--
作者：
Nakayama, S.;Semba, S.;Yokozaki, H.
我们以前已经表明，WW结构域含有氧化还原酶（WWOX）具有肿瘤抑制作用，其表达在胰腺癌中经常减少。在这项研究中，我们研究了WWOX表达的胰腺导管内乳头状粘液性肿瘤（IPMN），评估WWOX在胰管肿瘤发生的功能，使用免疫组化和甲基化特异性聚合酶链反应分析。在包括导管内乳头状粘液腺瘤（IPMAs）和导管内乳头状粘液癌（IPMCs）在内的41例IPMN中，在20例IPMAs中的3例（15%）和21例IPMCs中的17例（81%）中检测到WWOX免疫反应性丧失或降低。此外，在3个WWOX（-）IPMA中的1个（33%）和17个WWOX（-）IPMC中的9个（53%）中检测到WWOX调控位点的超甲基化，这表明超甲基化可能在WWOX表达抑制中起重要作用。WWOX表达的减少与较高的Ki-67标记指数显著相关，但与ssDNA凋亡小体指数无关。有趣的是，在这些IPMN中，WWOX表达的降低与SMAD 4表达的丧失显著相关。结果表明，WWOX调控区高甲基化导致WWOX表达下调对胰管转化至关重要。
We have previously shown that WW domain-containing oxidoreductase (WWOX) has tumour-suppressing effects and that its expression is frequently reduced in pancreatic carcinoma. In this study, we examined WWOX expression in intraductal papillary mucinous neoplasm of the pancreas (IPMN) to assess the function of WWOX in pancreatic duct tumourigenesis using immunohistochemistry and methylation-specific polymerase chain reaction analysis. Among 41 IPMNs including intraductal papillary mucinous adenomas (IPMAs) and intraductal papillary mucinous carcinomas (IPMCs), loss or reduced WWOX immunoreactivity was detected in 3 (15%) of 20 IPMAs and 17 (81%) of 21 IPMCs. In addition, hypermethylation of the WWOX regulatory site was detected in 1 (33%) of 3 WWOX(-) IPMAs and 9 (53%) of 17 WWOX(-) IPMCs, suggesting that hypermethylation may possibly be important in the suppression of WWOX expression. Reduction of WWOX expression was significantly correlated with a higher Ki-67 labelling index but was not correlated with the ssDNA apoptotic body index. Interestingly, decreased WWOX expression was significantly correlated with loss of SMAD4 expression in these IPMNs. The results indicate that downregulation of WWOX expression by the WWOX regulatory region hypermethylation is critical for transformation of pancreatic duct.