SOX2在乳腺癌细胞干性维持中转录调控机制研究

Breast cancer is a major cancer type in women. Breast cancer stem cells determine breast tumorigenesis and breast cancer development. Although SOX2 was reported to play a key role in breast tumorigenesis and breast cancer development via functioning as the key transcriptional factor in maintenance of stemness of breast cancer cells, it was largely unknown about how the expression of SOX2 was transcriptionally regulated in breast cancer cells. We found that SOX2 promoter contains the GATA transcription factor binding consensus sequence element. In breast cancers, the SOX2 expression level was found to be significantly negatively correlated with the expression of the atypical GATA transcription factor TRPS1. Our preliminary data shows that TRPS1 represses SOX2 expression via recognizing the GATA transcription factor binding consensus sequence element in the SOX2 promoter and recruiting Nucleosome Remodeling Deacetylase (NuRD) complex in breast cancer cells. In current proposal, we will further explore the mechanism of transcription regulation of SOX2 in maintenance of stemness of breast cancer cells during breast tumorigenesis and breast cancer development. We intend to uncover how SOX2 expression was transcriptional regulated in breast cancer to improve the understanding of molecular mechanism in stemness maintenance of breast cancer cells.

乳腺癌是女性最高发的癌症类型。乳腺癌干细胞是乳腺癌发生发展的基础。已有研究表明SOX2是乳腺癌细胞干性维持的关键因子，在乳腺癌发生发展中发挥关键作用，然而在乳腺癌细胞中SOX2的表达调控机制却不清楚。我们课题组初步研究结果表明SOX2启动子区含有GATA转录因子识别元件，在乳腺癌中非典型GATA转录因子TRPS1与SOX2表达负相关，TRPS1通过招募去乙酰化核小体重塑酶复合体（NuRD complex）在乳腺癌细胞中抑制SOX2的表达。本项目的研究中我们将在前期的工作基础上综合应用生物信息学、生化与分子生物学和细胞生物学等方法，结合小鼠模型和临床样本数据分析，从转录组学、蛋白质组学和表观遗传学等方面，进一步深入研究乳腺癌细胞中SOX2表达的转录调控机制及该机制在乳腺癌干细胞干性维持和乳腺癌发生发展中的作用，具有重要意义。

乳腺癌是女性最高发的癌症类型，现已成为全球第一高发癌症类型。乳腺癌干细胞是乳腺癌发生发展的基础。SOX2是乳腺癌细胞干性维持的关键因子，在乳腺癌发生发展中发挥关键作用，然而在乳腺癌细胞中SOX2的表达调控机制却不清楚。本项目首先通过生物信息学手段筛选获得TRPS1是抑制SOX2表达从而抑制肿瘤细胞干性维持和肿瘤发生的潜在重要转录因子；然后通过染色质免疫共沉淀和荧光素酶报告实验结果证实TRPS1能够直接结合在SOX2的启动子区域并且抑制启动子区域的转录活性；最后在体外细胞和体内小鼠实验证明TRPS1调控SOX2的表达抑制乳腺癌细胞的干性维持和肿瘤的发生。同时本项目未发表数据还提示CHD4通过形成NuRD 复合物和TRPS1互作共同抑制SOX2的表达从而调控乳腺癌细胞干性。综述所述，本项目的研究成果揭示了乳腺癌细胞中SOX2表达的转录调控机制及该机制在乳腺癌干细胞干性维持和乳腺癌发生发展中的重要作用。 本项目负责人作为通讯作者已发表包括JBC和BCR等基金号标注的研究性学术SCI论文8篇，其中第一标注4篇，第二标注4篇，这些研究论文已经被多个国际peer review的专业学术期刊论文所引用和正面评价，表明我们的研究成果已经对乳腺癌发生发展的机制研究产生一定的学术及社会影响，有重要的科学价值，同时我们本项目的研究还为后续开展的系统性深入研究乳腺癌病理机制和干预策略打下坚实的基础。