表遗传调控miR-491抑制mot-2在咖啡酸及其衍生物抗肝癌血管生成中的作用

膳食营养对恶性肿瘤的防治作用已日益受到关注，肝癌是我国当前社会重大公共卫生问题之一，血管生成是肝癌发生发展的根源，因此应用膳食营养抑制血管生成对肝癌的防治具有极其重要的意义。本项目根据前期工作积累，结合国内外文献报道，提出膳食中重要成分咖啡酸（CaA）及其衍生物抗肝癌血管生成的分子机制假说如下：CaA及其衍生物通过DNA去甲基化作用激活miR-491；miR-491靶向抑制mot-2而导致其下游JNKs/HIF-1α信号通路失活，阻滞肝癌细胞分泌VEGF，最终抑制肝癌细胞的血管生成能力。本项目拟从细胞、动物及人群水平系统地探讨上述分子过程在CaA及其衍生物抗肝癌血管生成中的作用机制，并进一步阐明血清miR-491、mot-2和VEGF在肝癌预后评估中的意义。为深入研究CaA及其衍生物抗肿瘤作用的分子机制、寻找肝癌的膳食干预靶标，及发现新的预后指标提供新思路。

Dietary prevention and treatment of cancer has been received more and more attention; Hepatocellular carcinoma (HCC) is one of the major public health issue in our country; The angiogenesis plays a key role in the initiation and development of HCC; So the dietary anti-angiogenesis has become a new strategy in the prevention and treatment of HCC. Caffeic acid (CaA) and its derivatives (CADs) are the important components of the diet. Here, based on our previous studies and on the researches worldwide, we suggest a new mechanism underlying the anti-angiogenesis induced by CaA and CADs. CaA and CADs elevate the expression of miR-491 by inducing the DNA demethylation, which targets and decreases the expression of mot-2. Mot-2 is an up-stream regulator of JNKs/HIF-1α signal pathway. Blocking of mot-2 causes an inactivation of JNKs/HIF-1α signal pathway, which attenuates the secretion of VEGF, and inhibits the angiogenesis of HCC cells. This project intends to perform the work in the cell model, animal model, as well as in the population. Meanwhile, we will also clarify the significance of the serum miR-491, mot-2 and VEGF in HCC prognosis. By understanding a new mechanism by which CaA and CADs block the angiogenesis of HCC, this project will expand our knowledge in the molecular mechanisms underlying the anti-tumor effects induced by CaA and CADs. Moreover, the project will also help to look for the new HCC dietary intervention targets, as well as to provide new ideas in the discovery of new prognostic indicators.