DNA羟化酶TET1在甲状腺癌发生发展中的作用及其分子机制

DNA羟化酶TET1将5甲基胞嘧啶（5-mC）氧化成5-羟甲基胞嘧啶（5-hmC），进而实现DNA去甲基化。其介导的表观遗传学事件参与多种肿瘤的发生与发展。有研究显示TET1在多种肿瘤中表达下调，与之相应的5-hmC水平也显著降低，提示TET1可能发挥抑癌作用。然而，该基因在甲状腺癌中的作用至今未见报道。本项目前期研究发现甲状腺癌组织中TET1的表达和5-hmC水平显著低于癌旁组织。过表达和敲除甲状腺癌细胞中TET1分别抑制和增强细胞增殖、克隆形成、迁移和侵袭能力，提示TET1可能是一个新的甲状腺癌抑制因子。同时，我们的研究还显示TET1可能在甲状腺癌细胞糖代谢及氧化还原稳态中发挥独特作用。基于此，本项目拟通过细胞及动物实验，进一步探讨甲状腺癌中TET1表达下调的分子机制，鉴定TET1抑癌机制的关键作用靶点，明确TET1参与肿瘤细胞糖代谢及氧化还原稳态的作用机制，绘制其基因/蛋白调控网络。

DNA hydroxylase TET1 is a dioxygenase that convert 5-methylcytosine (5-mC) to 5-hydroxylmethylcytosine (5-hmC), resulting in DNA demethylation. TET1-mediated epigenetic events play an important role in tumroigenesis. Recently, interesting clues on the role of TET proteins including TET1 in cancer formation are quickly emerging. It has been reported that loss of TET1 and 5-hmC in a broad spectrum of solid tumors, including breast cancer, hepatocarcinoma, melanoma, gastric cancer and colon cancer. These observations suggest that TET1 may be a potential tumor suppressor. However, the role of TET1 in thyroid carcinogenesis remains largely unknown. Our preliminary data showed that TET1 expression and 5-hmC levels were significantly down-regulated in thyroid cancer tissues as compared with matched normal thyroid tissues. Restoring TET1 expression in thyroid cancer cells significantly inhibited cell proliferation, colony formation, migration and invasion. Conversely, TET1 depletion promoted thyroid cancer cell growth and invasiveness. Taken together, these results suggest that TET1 should be a novel tumor suppressor in thyroid cancer. In addition, our data revealed that TET1 suppressed cellular generation of reactive oxygen species (ROS) and limited extracellular acidification, indicating that TET1 may play a role in tumor redox stasis and glucose metabolism. The aims of this project is to further explore biological role and molecular mechanisms of TET1 in thyroid tumorigenesis by using cell and mice models, and identify its downstream target genes using ChIP-Seq, gene expression microarray and Protein Chip approaches.