TIF1γ在结肠癌生长和肝转移中的双向作用及相关机制的研究

结肠癌是世界最常见的肿瘤之一，TGF-β/Smad 信号通路在结肠癌发生发展中发挥重要作用，而通路中的重要组成成分转录中介因子1γ（TIF1γ）在结肠癌的作用知之甚少。申请者发现：与正常结肠组织比较，TIF1γ的表达在早期结肠癌组织中明显上调，在进展期结肠癌组织中明显下调，这可能与表观遗传学调控有关。同时发现：TIF1γ促进早期结肠癌的生长，抑制进展期结肠癌的侵袭和肝转移，但机制尚不清楚。本课题将以人结肠癌组织和细胞系为研究对象，探讨TIF1γ在结肠癌发生发展中的双向作用及机制。一、分析不同发展阶段结肠癌组织及结肠癌细胞系中TIF1γ启动子区的甲基化态。二、研究调控结肠癌TIF1γ启动子区甲基化的机制。三、探讨TIF1γ启动子区甲基化和TIF1γ组蛋白修饰之间的相互调控机制。四、研究TIF1γ在结肠癌发挥双向作用的机制。本课题将加深对结肠癌发生发展机制的了解，为其多靶点联合治疗提供新思路。

Colon cancer (CC) is one of the most common malignancies worldwide. TGF-β /Smad signaling pathway plays a critical role in CC progression. As an important component of this pathway, the function of Transcriptional intermediary factor 1γ（TIF1γ）in CC is unclear. Our preliminary data demonstrated that TIF1γ expression is elevated in early stage of CC but significantly decreased in advanced CC compared to normal colon tissues. This may be controlled by epigenetic modification. Meanwhile, we found that TIF1γinhibits the growth of early stage of CC but promotes the invasion and liver metastasis of advanced CC. However, the underlying mechanism is unclear. This project will investigate the effects and related mechanisms of TIF1γ in the occurrence and progression of CC. Aim 1：To evaluate the methylation status of TIF1γ promoter in normal colon tissue, CC, liver metastatic CC specimen and CC cell lines. Aim 2：To study the mechanisms of TIF1γ promoter by methylation modification in CC. Aim 3：To investigate the relationship between the TIF1γ promoter methylation and histone acetylation in regulating the TIF1γ expression. Aim 4：To explore the understanding mechanisms by which TIF1γ plays a two-way role in the development of CC. This project will provide a new insight to the multi-targeting therapeutics for the liver metastasis of colon cancer.