SUMO化修饰对FOXK2的调控及其在乳腺癌发生发展中的分子机制研究

Breast cancer is a common malignant tumor in women, and its incidence is gradually increasing. In many big cities breast cancer has become the first female cancer, which is a serious threat to women's health and life. FOXK2 is a forkhead protein (forkhead box proteins, FOX) transcription factor. Recent studies suggest that FOXK2 plays important roles in chemotherapy drug resistance, and the generation and development of breast cancer. Our latest study shows that FOXK2 is a negative regulator of ERα, which can inhibit the proliferation of ERα-positive breast cancer cells, but its mechanism and biological function are still unclear, especially the molecular mechanisms in regulation of gene transcription, are still poorly understood. Therefore, the research focusing on the regulatory mechanism of FOXK2 is an important link to understand the pathogenesis of tumors, including breast cancer. This study will explore the Sumoylation of FOXK2, and its molecular mechanism on the regulation of ERα-mediated estrogen signaling pathway. We will also study the role of FOXK2 Sumoylation in the generation and development of breast cancer. This study will provide a theoretical evidence for elucidating the pathogenesis of breast cancer, and provide a new insight and targets for the prevention and treatment of breast cancer.

乳腺癌是女性常见的恶性肿瘤，在我国其发病率正逐年上升，在许多大城市已高居女性肿瘤的首位，严重威胁着妇女的健康和生命。FOXK2是一种插头蛋白转录因子，近年来的研究发现FOXK2在化疗药物抵抗和乳腺癌发生发展等过程中发挥重要作用。我们的最新研究表明FOXK2是ERα的一个负调控因子，能够抑制ERα阳性乳腺癌细胞的增殖，但其作用机理及生物学功能仍不十分清楚，特别是在基因转录调控的分子机制方面，仍知之甚少。因此，研究FOXK2的调控机制，是弄清乳腺癌等肿瘤发病机理的重要一环。本研究将探讨FOXK2的SUMO化修饰，及其对ERα介导的雌激素信号通路调控作用的分子机理，我们还将在整体动物水平研究FOXK2的SUMO化修饰在乳腺癌发生发展过程中的作用。通过以上研究将为阐明乳腺癌等恶性肿瘤的发病机理提供理论依据，为乳腺癌的预防、治疗提供新的思路和靶标。

乳腺癌是女性常见的恶性肿瘤，在我国其发病率正逐年上升，在许多大城市已高居女性肿瘤的首位，严重威胁着妇女的健康和生命。FOXK2是一种插头蛋白转录因子，近年来的研究发现FOXK2在化疗药物抵抗和乳腺癌发生发展等过程中发挥重要作用。我们的前期研究表明FOXK2是ERα的一个负调控因子，能够抑制ERα阳性乳腺癌细胞的增殖，但其作用机理及生物学功能仍不清楚，特别是在基因转录调控的分子机制方面，仍知之甚少。因此，研究FOXK2的调控机制，是弄清乳腺癌等肿瘤发病机理的重要一环。本研究通过免疫印迹、免疫共沉淀和定点突变等实验发现，FOXK2能够被SUMO3修饰，K527是其主要的修饰位点，SENP1能够介导FOXK2的去SUMO化。通过报告基因、免疫印迹和qRT-PCR等实验发现，SUMO化修饰能够增强FOXK2的转录活性和蛋白稳定性。另外，FOXK2的SUMO化修饰还能够下调ERα的蛋白水平，并抑制ERα的转录活性。最后，通过MTT和Trans-well等实验发现，FOXK2的SUMO化修饰能够抑制ERα阳性乳腺癌细胞的增殖和迁移。本研究为阐明乳腺癌等恶性肿瘤的发病机理提供了理论依据，为乳腺癌的预防、治疗提供了新的思路和靶标。