DIO2介导甲状腺激素T3调控胆固醇代谢促进乳腺癌肝转移的机制研究

整体研究目标：阐明碘化甲状腺原氨酸脱碘酶II (DIO2) 促进乳腺癌肝转移的分子机制，揭示甲状腺激素系统异常激活与乳腺癌特异性肝转移的关系。项目拟以乳腺癌肝转移动物模型和原代细胞系，乳腺癌肝转移临床样本和类器官为研究对象，探究DIO2介导胆固醇代谢促进乳腺癌肝转移的分子机制。运用小动物活体成像，乳腺癌肝转移动物模型，乳腺癌肝转移类器官，流式细胞术并整合RNA-seq, 脂质代谢组学，单细胞拉曼技术研究：1亲代乳腺癌细胞与乳腺癌肝转移细胞的基因表达差异；2 DIO2的表达上调与乳腺癌肝转移的关系；3 探究DIO2上调T3是否通过调控SREPB-2，增强LDLR的表达而影响胆固醇代谢，促进乳腺癌肝转移的分子机制。课题将在分子、细胞、动物和临床样本等层面解析DIO2调控乳腺癌特异性肝转移的新机制，将为寻找针对乳腺癌肝转移的治疗靶点提供新的研究思路和实验支撑，因而具有重要的科学和临床价值。

It has been vindicated that the activity of thyroid hormone system is critical involved in tumor immunosurveillance. And it was recently discovered in our study that the abnormal activation of thyroid hormone system can promote breast cancer liver metastasis (BCLM). Nevertheless, the DIO2 in thyroid hormone system involved in BCLM remains unknown. We thus seek to understand whether the upregulation of DIO2 in the thyroid hormone system plays a critical role in BCLM. In the current project, we intend to make use of BCLM mouse model and primary cells lines, BCLM clinical sample and organoids to clarify molecular mechanisms of the increase of DIO2 in cancer metastasis precisely, adopting a combination of techniques including in vivo imaging system, BCLM mouse model and organoid, flow cytometry and integrated RNA-seq, lipid metabolomics, single-cell Raman spectroscopy to address three major issues. Firstly, we will explore the different gene expression between parental breast cancer cells and BCLM cell lines. Secondly, we will confirm whether the upregulation of DIO2 is sufficient to promote BCLM and find out whether there is a causal link between the thyroid hormone system activation and BCLM. Lastly, we have proved that DIO2 increased T3 level and promoted BCLM in our research, whether SREPB-2 is mediated the increasing of LDLR and affects cholesterol metabolism to promote breast cancer liver metastasis is still unknown. The research will analyze the new mechanism of DIO2 regulating breast cancer-specific liver metastasis at different levels such as molecules, cells, whole animals and clinical samples, and will provide new research ideas and experimental support for finding therapeutic targets for breast cancer liver metastasis. Therefore, it has important scientific and clinical value.