天花粉蛋白调控miRNAs甲基化抑制宫颈癌上皮间质转化的实验研究

Epithelial-mesenchymal transition (EMT) is an important biological processe by which the epithelial cell-derived tumor cells obtain their abilities for migration and invasion. To clarifing underlying molecular mechanism of EMT and explore the EMT key molecular-based therapy are the major scientific issues in the cancer researches. miRNA is a class of signaling molecules involved in the regulation of gene expression. The recent research found that abnormal expression of some miRNA genes closely related with EMT. Also in the promoter region of these miRNA genes, there are multiple methylation sites, suggesting that the methylation of miRNAs promoter site may be an important process in EMT regulation. Our preliminary works found that trichosanthin (TCS), an active ingredient of traditional chinese medicine, could effectively inhibit the expression and activity of DNA methyltransferase 1 (Dnmt1) and demethylate multiple tumor suppressor genes. On this basis, our project intends to further, in the level of cells, tissues and animals, analysis ability of TCS in affecting expression of the relevant miRNA by inhibiting their protmoter methylation, which in turn inhibit tumor cell's EMT process. The successful implementation of this project will help to clarify the importance of DNA methylation in tumor cell's EMT and supply the new way for clinical treatment of tumor invasion and metastasis.

上皮间质转化(EMT)是上皮细胞来源的肿瘤细胞获得迁移和侵袭能力的重要生物学过程，阐明EMT发生的分子机制，探索基于EMT关键分子的治疗手段是当前肿瘤防治研究中的重大科学问题。miRNA是一类参与基因表达调控的信号分子，新近研究发现，部分miRNA基因的异常表达与EMT发生密切相关，且这些基因的启动子内存在大量甲基化位点，提示miRNAs启动子区域甲基化可能是调控EMT过程重要病理过程。本项目前期研究发现，中药有效成分天花粉蛋白（TCS）可有效抑制DNA甲级转移酶1（Dnmt1）表达及活性，对多种抑癌基因具有去甲基化作用。在此基础上，本项目拟进一步在细胞、组织和动物水平上，分析TCS能否通过抑制miRNAs启动子甲基化促进miRNAs表达，继而抑制肿瘤细胞的EMT过程。本项目的成功实施，将有助于阐明DNA甲基化在肿瘤细胞EMT发生中的重要性，为临床上抑制肿瘤侵袭和转移提供新的治疗手段。

上皮间质转化(EMT)是上皮细胞来源的肿瘤细胞获得迁移和侵袭能力的重要生物学过程，阐明EMT发生的分子机制，探索基于EMT关键分子的治疗手段是当前肿瘤防治研究中的重大科学问题。miRNA是一类参与基因表达调控的信号分子，新近研究发现，部分miRNA基因的异常表达与EMT发生密切相关，且这些基因的启动子内存在大量甲基化位点，提示DNA甲基化可通过对miRNA 的调控而影响EMT过程。本项目旨在细胞水平上，分析EMT对宫颈癌细胞增殖和侵袭转移能力的影响，以及中药有效成分天花粉蛋白（TCS）通过其去DNA甲基化活性而影响相关miRNA表达，继而抑制宫颈癌细胞EMT过程的分子基础。本项目的研究成果将有助于阐明TCS抗肿瘤活性的药理学机制，将为TCS用于临床宫颈癌治疗提供实验支撑。