lncRNA-HOST2—USP15—VGLL4轴促进乳腺癌肝转移的机制研究

lncRNA的异常表达与乳腺癌的远处转移关系密切。前期研究显示，lncRNA-HOST2在乳腺癌肝转移组织中明显升高并促进乳腺癌肝转移，VGLL4可抑制乳腺癌肝转移。HOST2可与RNA结合蛋白HuR结合抑制VGLL4表达；同时通过BioSITE联合质谱技术，筛选出了VGLL4的互作蛋白USP15，并初步发现HOST2可调控USP15的转录活性。. 本课题拟：体外、体内实验验证HOST2在乳腺癌中的生物学功能及对肝转移的影响；采用RNAi、ChIP、质谱、CRISPR/Cas9等技术明确HOST2—HuR复合物调控USP15转录影响VGLL4的机制及m6A修饰对HOST2的表观调控机制。最终明确HOST2—USP15—VGLL4轴调控乳腺癌肝转移的机制，为乳腺癌治疗提供潜在的靶点、为其诊断及预后判断筛选出可能的标志物。

The abnormal expression of lncRNA is strongly associated with breast cancer distant metastasis. Previous studies have shown that lncRNA-HOST2 was over-expressed in liver metastasis tissues of breast cancer patients. Also, lncRNA-HOST2 promoted the occurrence of breast cancer liver metastasis, while VGLL4 inhibited it. HuR is an RNA binding protein. Importantly, a HOST2-HuR combination could inhibit VGLL4 expression. Moreover, using BioSITE technique, we found that USP15 transcription activity could be regulated by HOST2, at the same time. USP15 is connected with VGLL4 in the protein-protein interaction map..The purpose of this study is to explore the biological function of HOST2 in breast cancer, and its effects on liver metastasis in vivo and in vitro. The techniques of RNAi, ChiP, proteomic, CRISPR/Cas9 would be used to confirm the mechanism of HOST2-HuR combination in regulating USP15 transcription, which influences VGLL4 expression, and to explore the effect of m6A modification in influencing HOST2 function. Finally, the mechanism of how the lncRNA-HOST2—USP15—VGLL4 axis regulates breast cancer liver metastasis could be confirmed. This could provide a novel possible targeted treatment, and could be acted as a potential diagnostic and prognostic biomarker in breast cancer.