ZIC1 Is a Putative Tumor Suppressor in Thyroid Cancer by Modulating Major Signaling Pathways and Transcription Factor FOXO3a
ZIC1 Is a Putative Tumor Suppressor in Thyroid Cancer by Modulating Major Signaling Pathways and Transcription Factor FOXO3a
复制标题
ZIC1 通过调节主要信号通路和转录因子 FOXO3a 被认为是甲状腺癌中的肿瘤抑制因子
DOI：
10.1210/jc.2013-3729
复制
发表时间：
2014-07-01
影响因子：
5.8
通讯作者：
Hou, Peng
中科院分区：
文献类型：
--
作者：
Qiang, Wei;Zhao, Yuan;Hou, Peng
背景：据报道，ZIC1在一些脑肿瘤中过度表达并起致瘤作用，而在胃癌和结直肠癌中，ZIC1因启动子超甲基化而失活，并作为肿瘤抑制因子。然而，到目前为止，它在甲状腺癌中的生物学作用仍然完全未知。目的：探讨ZIC1在甲状腺癌变中的生物学功能及相关分子机制。设置与设计：采用定量RT-PCR （qRT-PCR）检测所研究基因的mRNA表达情况。采用甲基化特异性PCR分析ZIC1基因启动子甲基化。通过细胞增殖与集落形成、细胞周期与凋亡、细胞迁移与侵袭等实验研究异位ZIC1在甲状腺癌细胞中的表达功能。结果：ZIC1在原发性甲状腺癌组织和甲状腺癌细胞系中均因启动子高甲基化而频繁下调。此外，我们的数据显示ZIC1高甲基化与甲状腺乳头状癌患者的淋巴结转移显著相关。值得注意的是，恢复ZIC1在甲状腺癌细胞中的表达可通过阻断磷脂酰肌醇-3激酶(PI3K)/Akt和RAS/RAF/MEK/ERK （MAPK）通路的活性，增强FOXO3a的转录活性，显著抑制细胞增殖、集落形成、迁移和侵袭，诱导细胞周期阻滞和凋亡。结论：我们的数据表明ZIC1经常因启动子高甲基化而失活，并通过调节PI3K/Akt和MAPK信号通路以及转录因子FOXO3a在甲状腺癌中发挥抑癌作用。
Context: ZIC1 has been reported to be overexpressed and plays an oncogenic role in some brain tumors, whereas it is inactivated by promoter hypermethylation and acts as a tumor suppressor in gastric and colorectal cancers. However, until now, its biological role in thyroid cancer remains totally unknown.Objectives: The aim of this study is to explore the biological functions and related molecular mechanism of ZIC1 in thyroid carcinogenesis.Setting and Design: Quantitative RT-PCR (qRT-PCR) was performed to evaluate mRNA expression of investigated genes. Methylation-specific PCR was used to analyze promoter methylation of the ZIC1 gene. The functions of ectopic ZIC1 expression in thyroid cancer cells were determined by cell proliferation and colony formation, cell cycle and apoptosis, as well as cell migration and invasion assays.Results: ZIC1 was frequently down-regulated by promoter hypermethylation in both primary thyroid cancer tissues and thyroid cancer cell lines. Moreover, our data showed that ZIC1 hypermethylation was significantly associated with lymph node metastasis in patients with papillary thyroid cancer. Notably, restoration of ZIC1 expression in thyroid cancer cells dramatically inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrest and apoptosis by blocking the activities of the phosphatidylinositol-3-kinase (PI3K)/Akt and RAS/RAF/MEK/ERK (MAPK) pathways, and enhancing FOXO3a transcriptional activity.Conclusions: Our data demonstrate that ZIC1 is frequently inactivated by promoter hypermethyaltion and functions as a tumor suppressor in thyroid cancer through modulating PI3K/Akt and MAPK signaling pathways and transcription factor FOXO3a.