转录协调因子Mybbp1a调控LRP12依赖的TGF-β/SMAD信号通路活化促进肝癌转移的分子机制研究

TGF-β/SMAD信号通路诱导的上皮-间质转化是肝癌细胞侵袭转移的关键环节。我们发现敲低Mybbp1a对肝癌细胞TGF-β/SMAD信号通路影响尤为明显，但是具体的调控机制尚不清楚。研究表明CUB结构域能够与TGF-βRII特异性结合并促进TGF-βRII活化，我们发现敲低Mybbp1a能够明显抑制肝癌细胞内LRP12的表达水平，且研究表明LRP12的胞外段存在CUB结构域。因此我们提出假说：Mybbp1a调控LRP12依赖的TGF-β/SMAD信号通路活化促进肝癌转移。为证实以上假说，本研究拟构建裸鼠肝癌肺转移模型，通过GST pull down、Co-IP等实验手段，明确Mybbp1a与LRP12、TGF-β/SMAD信号通路的调控关系，证明LRP12通过特异性结合TGF-βRII促进TGF-β/SMAD信号通路活化。本研究丰富肝癌转移的分子机制，为寻找特异性治疗靶标提供新的思路。

The epithelial-mesenchymal transition induced by TGF-β/SMAD signaling pathway is a key link in the invasion and migration of liver cancer cells. We found that knocking down Mybbp1a has a particularly significant effect on the TGF-β/SMAD signaling pathway in liver cancer cells, however, the specific regulatory mechanism is still unclear. Studies have shown that the CUB domain can specifically bind to TGF-βRII and promote the activation of TGF-βRII. We found that knocking down Mybbp1a can significantly inhibit the expression of LRP12 in liver cancer cells, and studies have demonstrated that there is a CUB domain in the extracellular segment of LRP12. Therefore, we put forward the hypothesis: Mybbp1a regulates the activation of LRP12-dependent TGF-β/SMAD signaling pathway to promote liver cancer metastasis. In order to confirm the above hypothesis, this study intends to construct a nude mouse liver cancer lung metastasis model. Through experimental methods such as GST pull down and Co-IP, the regulatory relationship between Mybbp1a and LRP12 and TGF-β/SMAD signaling pathways is clarified, and proved that LRP12 could bind specifically TGF-βRII to promote the activation of TGF-β/SMAD signaling pathway. This study enriches the molecular mechanisms of liver cancer metastasis and provides new ideas for finding specific therapeutic targets.