TET1 通过介导 DNA 的羟甲基化激活 Wnt/β-catenin 信号通路的抑制剂，从而抑制胰腺肿瘤细胞中的 EMT。
TET1-mediated DNA hydroxymethylation activates inhibitors of the Wnt/β-catenin signaling pathway to suppress EMT in pancreatic tumor cells.
机构信息
Department of General Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Research Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
出版信息
J Exp Clin Cancer Res. 2019 Aug 9;38(1):348. doi: 10.1186/s13046-019-1334-5.
BACKGROUND
Ten-eleven translocation 1 (TET1) is a dioxygenase that converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) to induce DNA demethylation. TET1 has been reported to be absent in cancers, and to influence various oncogenes and anti-oncogenes. However the function of TET1 in pancreatic tumor remains poorly understood. In this study, we investigated the role of TET1 in the progression of pancreatic tumor and its mechanism of tumor suppression.
METHODS
Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) staining and dot blot were performed to detect the TET1 and 5-hmC expression in pancreatic tumor tissues and its adjacent non-tumor tissues. The clinical parameters significance of pancreatic tumor tissues was determined statistically. TET1 over-expression and knock-out cell lines were built and confirmed in vitro. Cell proliferation assay, wound-healing assays, transwell migration assay and nude mice model of orthotopic pancreatic cancer implantation were performed to assess the function of TET1 in pancreatic tumor. Western blot, qRT-PCR, immunofluorescence (IF), bisulfate sequencing (BSP), Chromatin immunoprecipitation (ChIP) were used to uncover the mechanism.
RESULTS
TET1 levels and 5-hmC content were downregulated in pancreatic tumor tissues and cell lines, and pancreatic tumor patients with low TET1 levels had a shorter overall survival than patients with high levels of TET1. TET1 suppressed pancreatic tumor proliferation and metastasis in vivo and in vitro. TET1 bound to the secreted frizzled-related protein 2 (SFRP2) promoter and catalyzed demethylation to activate transcription of SFRP2, inhibiting both the canonical and non-canonical Wnt signaling pathways, and ultimately obstructing epithelial-mesenchymal transition (EMT) in pancreatic tumors.
CONCLUSION
We found TET1 plays as a suppressor in pancreatic tumor progression via obstructing Wnt signaling pathways.
背景
十 - 十一易位 1（TET1）是一种双加氧酶，可将 5-甲基胞嘧啶（5-mC）转化为 5-羟甲基胞嘧啶（5-hmC），从而诱导 DNA 去甲基化。据报道，TET1 在癌症中不存在，并影响各种癌基因和抑癌基因。然而，TET1 在胰腺肿瘤中的功能仍知之甚少。在这项研究中，我们研究了 TET1 在胰腺肿瘤进展中的作用及其肿瘤抑制机制。
方法
采用定量实时 PCR（qRT-PCR）、免疫组织化学（IHC）染色和点印迹法检测胰腺肿瘤组织及其相邻非肿瘤组织中 TET1 和 5-hmC 的表达。统计分析胰腺肿瘤组织的临床参数意义。体外构建和验证 TET1 过表达和敲除细胞系。通过细胞增殖试验、划痕愈合试验、Transwell 迁移试验和原位胰腺癌细胞植入裸鼠模型评估 TET1 在胰腺肿瘤中的功能。Western blot、qRT-PCR、免疫荧光（IF）、亚硫酸氢盐测序（BSP）、染色质免疫沉淀（ChIP）用于揭示机制。
结果
TET1 水平和 5-hmC 含量在胰腺肿瘤组织和细胞系中下调，TET1 水平低的胰腺肿瘤患者总生存期短于 TET1 水平高的患者。TET1 在体内和体外均抑制胰腺肿瘤的增殖和转移。TET1 结合分泌卷曲相关蛋白 2（SFRP2）启动子并催化去甲基化以激活 SFRP2 的转录，抑制经典和非经典 Wnt 信号通路，最终阻止胰腺肿瘤中的上皮-间充质转化（EMT）。
结论
我们发现 TET1 通过阻断 Wnt 信号通路在胰腺肿瘤进展中发挥抑制作用。
Zotero 插件