Loss of CDX2 gene expression is associated with DNA repair proteins and is a crucial member of the Wnt signaling pathway in liver metastasis of colorectal cancer.
Loss of CDX2 gene expression is associated with DNA repair proteins and is a crucial member of the Wnt signaling pathway in liver metastasis of colorectal cancer.
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DOI：
10.3892/ol.2018.7756
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发表时间：
2018-03
期刊：
影响因子：
2.9
通讯作者：
Tiszlavicz L
中科院分区：
文献类型：
--
作者：
Tóth C;Sükösd F;Valicsek E;Herpel E;Schirmacher P;Tiszlavicz L
尾型同源异型盒2（CDX 2）已被公认为结直肠癌（CRC）的诊断标志物;然而，对其调控，特别是其与DNA修复蛋白、腺瘤性结肠息肉病（APC）和β-连环蛋白以非转录方式的潜在相互作用知之甚少。在本研究中，CDX 2的蛋白表达进行了分析，这取决于DNA修复蛋白，错配修复（MMR），O 6-甲基鸟嘌呤DNA甲基转移酶（MGMT）和切除修复交叉互补1（ERCC 1）的表达，并确定其在Wnt信号传导中的重要性。共101个肝转移瘤被冲压成组织芯片（TMA）块，并连续切片进行免疫组化。对于每种蛋白质，根据文献数据生成免疫反应性评分，并将评分与TMA拟合。随后，进行统计学分析以将表达水平相互比较并与临床数据进行比较。在38.5%的CRC肝转移病例中观察到CDX 2表达缺失。观察到CDX 2与每种研究的MMR之间的统计学显著关联：MutL同源物1（P<0.01）、MutS蛋白同源物（MSH）2（P<0.01）、MSH 6（P<0.01），并且减数分裂后分离增加2（P=0.040）。此外，MGMT和ERCC 1的丢失也与CDX 2的丢失相关（分别为P=0.039和P<0.01）。此外，CDX 2和ERCC 1与转移性肿瘤大小呈负相关（分别为P=0.038和P=0.027）。CDX 2的持续表达与细胞质/膜β-catenin和细胞核APC的高表达相关（分别为P=0.042和P<0.01）。总之，CDX 2表达缺失在CRC肝转移中并不罕见，结果表明CDX 2可能参与导致DNA修复蛋白表达缺失的机制，进而参与甲基化;然而，其在这种情况下的确切功能仍有待阐明。
Caudal type homeobox 2 (CDX2) has been well-established as a diagnostic marker for colorectal cancer (CRC); however, less is known about its regulation, particularly its potential interactions with the DNA repair proteins, adenomatous polyposis coli (APC) and β-catenin, in a non-transcriptional manner. In the present study, the protein expression of CDX2 was analyzed, depending on the expression of the DNA repair proteins, mismatch repair (MMR), O6-methylguanine DNA methyltransferase (MGMT) and excision repair cross-complementing 1 (ERCC1), and its importance in Wnt signaling was also determined. A total of 101 liver metastases were punched into tissue microarray (TMA) blocks and serial sections were cut for immunohistochemistry. For each protein, an immunoreactive score was generated according to literature data and the scores were fitted to TMA. Subsequently, statistical analysis was performed to compare the levels of expression with each other and with clinical data. CDX2 loss of expression was observed in 38.5% of the CRC liver metastasis cases. A statistically significant association between CDX2 and each of the investigated MMRs was observed: MutL Homolog 1 (P<0.01), MutS protein Homolog (MSH) 2 (P<0.01), MSH6 (P<0.01), and postmeiotic segregation increased 2 (P=0.040). Furthermore, loss of MGMT and ERCC1 was also associated with CDX2 loss (P=0.039 and P<0.01, respectively). In addition, CDX2 and ERCC1 were inversely associated with metastatic tumor size (P=0.038 and P=0.027, respectively). Sustained CDX2 expression was associated with a higher expression of cytoplasmic/membranous β-catenin and with nuclear APC expression (P=0.042 and P<0.01, respectively). In conclusion, CDX2 loss of expression was not a rare event in liver metastasis of CRC and the results suggested that CDX2 may be involved in mechanisms resulting in the loss of DNA repair protein expression, and in turn methylation; however, its exact function in this context remains to be elucidated.
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