TGIF1在乳腺癌转移中的生物学作用及分子机制研究

TGIF1 is an important transcription factor, which is involved in occurance and metastasis of various types of cancer. In this study, we will focus on to explore the association between TGIF1 and breast cancer metastasis and its related molecular mechanism on the base of four aspects such as moleculer level, cellular level, animal model and population study. First, we will observe the difference in migration and invasion between TGIF1 overexpressed/silenced breast cancer cells and their controls correspondingly. Secondly, we will observe the difference in metastasis between TGIF1 overexpressed/silenced breast cancer cells and their controls correspondingly in vivo. Thirdly, we will observe the correlation of Twist expression with TGIF1 expression in human breast cancer samples and the correlation of TGIF1 expression with different histological type, stage and metastatic status. At last, we will explore the molecular mechanism of the effects of TGIF1 on Twist expression.

TGIF1是一种重要的转录调控因子，其表达失常与肿瘤的发生和转移有关。本研究从分子水平、细胞水平、整体动物和人群研究四个层面探讨TGIF1与乳腺癌发生转移之间的关系及其分子生物学机制。首先，以两种高度转移的乳腺癌细胞(4T1和MDA-MB-231)为模型构建TGIF1低表达细胞株和以低转移的人乳腺癌细胞(MCF-7)为模型构建TGIF1过表细胞株，观察细胞体外迁移及侵袭能力变化；其次，动物体内实验观察TGIF1过表达/低表达的乳腺癌细胞在体内发生转移的差异；进一步，在人群乳腺癌组织标本中观察TGIF1和Twist表达及TGIF1与不同肿瘤病理类型、肿瘤分期和肿瘤转移状态的关系；最后，本研究在分子水平深入探讨TGIF1对Twist表达调控的分子机制。

乳腺癌是当今女性最常见的恶性肿瘤，而肿瘤发生浸润转移是乳腺癌病人的死亡主要原因。TGIF（即TGIF1）与肝癌、肺癌及尿道上皮细胞癌的浸润转移有关，但在乳腺癌浸润转移中的生物学作用还不清楚。本研究构建TGIF稳定过表达和低表达的乳腺癌细胞株，采用体内体外实验及人群研究评价TGIF在乳腺癌浸润转移中的生物学作用及分子机制。结果显示，沉默TGIF抑制了乳腺癌细胞（4T1和MDA-MB-231）体外迁移及浸润，过表达TGIF促进了乳腺癌细胞（4T1和MCF-7）体外迁移及浸润；裸鼠肺转移模型结果显示，沉默TGIF抑制了乳腺癌细胞（4T1和MDA-MB-231）在裸鼠肺部转移瘤结节的形成，过表达TGIF促进了乳腺癌细胞（4T1和MCF-7）在裸鼠肺部转移瘤结节的形成；人群研究结果显示，TGIF高表达率在转移性乳腺癌病人乳腺组织标本中比非转移性乳腺癌病人乳腺组织标本中明显升高。Twist是乳腺癌浸润转移的调节因子，本课题进一步探讨TGIF对Twist表达调控作用；结果表明，TGIF过表达能够上调Twist蛋白和mRNA表达，而沉默TGIF后能够下调Twist蛋白和mRNA表达，但报告基因实验和染色体免疫共沉淀实验结果显示TGIF与Twist基因启动子区没有相互作用。本研究结果提示TGIF通过调控Twist表达促进乳腺癌浸润转移；该结果为乳腺癌转移的预防、早期诊断、分子分型以及选择合适靶点进行干预和治疗提供新的理论依据。