MLKL介导的程序性细胞坏死对乳腺癌转移的作用和分子机制研究

Necroptosis is a form of regulated caspase-independent cell death that is mediated by death receptors. During the necroptosis, the receptor kinases RIP1 and RIP3 form a kinase complex and then phosphorylates the downstream factor MLKL. Phosphorylated MLKL is translocated to the plasma membrane and directly ruptures the plasma membrane, which is an essential step for necroptotic cell death. Due to the rupture of plasma membrane, the release of intracellular contents from necroptotic cells elicit inflammatory responses in vivo. Cancer is an inflammation-related disease, however, the role of necroptosis in cancer development is currently unknown. Our pilot study detected the phosphorylation of MLKL in necrotic breast tumor tissues. Importantly, by using multiple mouse models for breast cancer, we found that knockout of MLKL inhibited breast tumor metastasis. Bases on these preliminary discoveries, we plan to further study the role of necroptosis in breast cancer metastasis and related molecular mechanisms by using our established mouse models and clinic breast cancer species. This study will provide a very important theoretic basis for clinically developing therapeutic treatment for necroptosis-related cancer.

程序性细胞坏死是一种由死亡受体介导的、Caspase蛋白水解酶非依赖性的细胞死亡方式，其调控机制以及相关疾病是近年研究热点。研究表明，蛋白激酶RIP1 和RIP3 形成复合体并激活下游细胞信号转导是程序性细胞坏死的关键步骤。申请人前期鉴定出RIP3激酶下游靶蛋白MLKL，MLKL被RIP3多聚化后直接定位细胞膜上导致细胞膜破裂，内容物释放，诱发炎症反应。癌症是炎症相关疾病，由此我们推断程序性细胞坏死参与肿瘤发生发展过程。本课题组前期研究发现MLKL在乳腺癌坏死组织中高表达并被磷酸化激活；在小鼠乳腺癌原位移植瘤和小鼠自发乳腺肿瘤组织中敲除MLKL，乳腺肿瘤转移被明显抑制。本课题将前期工作基础上，从体内、体外、临床病人肿瘤组织不同角度系统性地阐明程序性细胞坏死在乳腺肿瘤转移中的作用和分子机制。本项目的开展为阐明乳腺癌的发生发展机理以及靶向程序性细胞坏死开发肿瘤干预手段提供重要科学依据。

本项目以乳腺癌为肿瘤模型研究程序性细胞坏死在乳腺癌发生发展中的作用和分子机制。在本项目中我们发现程序性细胞坏死在晚期乳腺癌中被诱导发生。我们进一步发现抑制程序性细胞坏死能显著抑制乳腺癌的转移，并且这一作用是由于肿瘤免疫微环境的改变而导致。通过对小鼠和人类乳腺癌肿瘤样本的研究，我们发现低糖诱发了肿瘤细胞的程序性坏死，并且这种坏死是由ZBP1-RIPK3-MLKL信号分子所介导。通过对人类临床数据库分析，我们发现高表达ZBP1、RIPK3和MLKL与乳腺癌患者的不良预后相关。因此，本项目首次解析了程序性细胞坏死在乳腺癌发生发展中的作用和分子机制，为靶向程序性细胞坏死开发肿瘤干预手段提供重要科学依据。