ZIC1 is downregulated through promoter hypermethylation, and functions as a tumor suppressor gene in colorectal cancer.
ZIC1 is downregulated through promoter hypermethylation, and functions as a tumor suppressor gene in colorectal cancer.
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ZIC1 通过启动子高甲基化下调，并在结直肠癌中充当肿瘤抑制基因
DOI：
10.1371/journal.pone.0016916
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发表时间：
2011-02-15
期刊：
影响因子：
3.7
通讯作者：
Jin H
中科院分区：
文献类型：
--
作者：
Gan L;Chen S;Zhong J;Wang X;Lam EK;Liu X;Zhang J;Zhou T;Yu J;Si J;Wang L;Jin H
小脑锌指蛋白（ZIC 1）是一种转录因子，在脊椎动物的发育过程中起着至关重要的作用。最近，还发现ZIC 1参与人类癌症的进展，包括髓母细胞瘤、子宫内膜癌和间质肿瘤。然而，ZIC 1在结肠癌进展中的功能尚未确定。在这项研究中，我们证明了ZIC 1在结肠癌细胞系中被沉默或显著下调。5-氮-2 ′-脱氧胞苷（Aza）去甲基化可逆转上述效应。相对于邻近的非肿瘤组织，原发性结直肠癌组织中的ZIC 1表达也显著下调（p = 0.0001）。 此外，ZIC 1基因启动子甲基化在原发肿瘤组织中频繁检测到（85%，34/40），而在邻近非肿瘤组织中未检测到。ZIC 1的异位表达抑制细胞增殖并诱导细胞凋亡，这与MAPK和PI 3 K/Akt通路以及Bcl-xl/Bad/Caspase 3级联相关。为了确定ZIC 1的候选靶基因，我们使用cDNA微阵列，发现ZIC 1的异位表达下调了337个基因，上调了95个基因，并通过qRT-PCR验证了10个基因的表达。综上所述，我们的研究结果表明，ZIC 1可能作为一个肿瘤抑制基因，这是通过在结直肠癌启动子甲基化下调。
The transcription factor, Zinc finger of the cerebellum (ZIC1), plays a crucial role in vertebrate development. Recently, ZIC1 has also been found to participate in the progression of human cancers, including medulloblastomas, endometrial cancers, and mesenchymal neoplasms. However, the function of ZIC1 in colon cancer progression has not been defined. In this study, we demonstrate ZIC1 to be silenced or significantly downregulated in colon cancer cell lines. These effects were reversed by demethylation treatment with 5-aza-2′-deoxycytidine (Aza). ZIC1 expression is also significantly downregulated in primary colorectal cancer tissues relative to adjacent non-tumor tissues (p = 0.0001). Furthermore, methylation of ZIC1 gene promoter is frequently detected in primary tumor tissues (85%, 34/40), but not in adjacent non-tumor tissues. Ectopic expression of ZIC1 suppresses cell proliferation and induces apoptosis, which is associated with MAPK and PI3K/Akt pathways, as well as the Bcl-xl/Bad/Caspase3 cascade. To identify target candidates of ZIC1, we employed cDNA microarray and found that 337 genes are downregulated and 95 genes upregulated by ectopic expression of ZIC1, which were verified by 10 selected gene expressions by qRT-PCR. Taken together, our results suggest that ZIC1 may potentially function as a tumor suppressor gene, which is downregulated through promoter hypermethylation in colorectal cancers.
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