Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma- carcinoma sequence of the colorectum
Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma- carcinoma sequence of the colorectum
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DOI：
10.1038/modpathol.2014.41
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发表时间：
2015-01-01
期刊：
影响因子：
7.5
通讯作者：
Watanabe, Sumio
中科院分区：
文献类型：
--
作者：
Murakami, Takashi;Mitomi, Hiroyuki;Watanabe, Sumio
无蒂锯齿状腺瘤/息肉（SSA/P）被认为是导致结直肠癌发展的锯齿状瘤形成途径的早期前体。传统的腺瘤-癌序列与WNT信号通路的激活有关，尽管其在锯齿状病变中的作用仍有争议。为了阐明WNT信号转导激活与MLH1甲基化或BRAF/KRAS突变相关的锯齿途径和常规途径之间的差异，我们进行了β-连环蛋白免疫染色，MLH1和WNT信号转导相关基因（如AXIN 2、APC和MCC）和分泌型卷曲相关蛋白（SFRP）的甲基化特异性PCR，以及27个SSA/P中BRAF/KRAS的直接测序，14例SSA/Ps伴高度异型增生，9例SSA/Ps伴粘膜下癌; 19例常规腺瘤，26例高度异型增生腺瘤，25例粘膜下癌腺瘤。锯齿状系列的细胞核β-连环蛋白标记显著低于腺瘤，从SSA/Ps到高度异型增生或粘膜下癌，这些标记显著增加。SSA/P组MLH 1和SFRP 4甲基化频率显著高于相应腺瘤组。AXIN2和MCC在高度异型增生的SSA/Ps和粘膜下癌中的甲基化频率高于腺瘤。从高度异型增生的SSA/Ps到粘膜下癌，AXIN2和MCC甲基化逐步增加。在SSA/P系列中，细胞核β-连环蛋白表达与AXIN 2或MCC甲基化之间存在显著相关性。与腺瘤组相比，SSA/P组BRAF突变更常见，而KRAS突变较少见。SSA/P家系中BRAF突变与AXIN2甲基化呈负相关。总之，由SFRP 4、MCC和AXIN 2甲基化介导的WNT/β-连环蛋白信号激活可能在锯齿状和常规途径之间对结直肠肿瘤形成做出不同的贡献。
Sessile serrated adenoma/polyp (SSA/P) is considered as an early precursor in the serrated neoplasia pathway leading to colorectal cancer development. The conventional adenoma-carcinoma sequence is associated with activation of the WNTsignaling pathway, although its role in serrated lesions is still controversial. To clarify differences in WNT signaling activation in association with MLH1 methylation or BRAF/KRAS mutations between serrated and conventional routes, we performed beta-catenin immunostaining, methylation-specific PCR for MLH1 and WNT signaling associated genes such as AXIN2, APC, and MCC and secreted frizzled-related proteins (SFRPs), and direct sequencing of BRAF/KRAS in 27 SSA/Ps, 14 SSA/Ps with high-grade dysplasia and 9 SSA/Ps with submucosal carcinoma, as well as 19 conventional adenomas, 26 adenomas with high-grade dysplasia and 25 adenomas with submucosal carcinoma. Nuclear beta-catenin labelings were significantly lower in the serrated series than in their adenoma counterparts, and a significant increment in those labelings was found from SSA/Ps to those with high-grade dysplasia or submucosal carcinoma. The frequency of MLH1 and SFRP4 methylation was significantly higher in SSA/P series, as compared with corresponding adenoma series. AXIN2 and MCC were more frequently methylated in SSA/Ps with high-grade dysplasia and those with submucosal carcinoma than in adenoma counterparts. Stepwise increment of AXIN2 and MCC methylation was identified from SSA/Ps through those with high-grade dysplasia to those with submucosal carcinoma. A significant correlation was seen between nuclear beta-catenin expression and methylation of AXIN2 or MCC in the SSA/P series. BRAF mutation was more frequent, whereas KRAS mutation was less frequent in the SSA/P series as compared with the adenoma series. There was an inverse association of BRAF mutation with AXIN2 methylation in SSA/P series. In conclusion, WNT/beta-catenin signal activation mediated by the methylation of SFRP4, MCC, and AXIN2 may make different contributions to colorectal neoplasia between the serrated and conventional routes.