HBXIP调控非肌肉型肌球蛋白NMHC-IIA翻译后修饰介导的解聚作用在乳腺癌转移中的作用及分子机制研究

蛋白质翻译后修饰的改变与肿瘤的发生发展密切相关，阐明其作用及调控机制已成为国际研究热点。非肌肉肌球蛋白重链IIA（NMHC-IIA）在肿瘤中高表达，其纤维丝的聚合和解聚影响肿瘤细胞运动。然而，调控NMHC-IIA高表达和纤维丝变化的分子机制尚不清楚。本申请前期工作发现NMHC-IIA在乳腺癌转移组织中显著高表达，与患者生存期呈负相关，癌蛋白HBXIP与NMHC-IIA直接结合促进其纤维丝解聚致使细胞板状伪足形成增加。本申请拟以乳腺癌为研究对象，从分子、细胞、组织和动物模型等层面深入开展以下研究：确定HBXIP在乳腺癌中上调NMHC-IIA表达促进乳腺癌转移的作用；明确NMHC-IIA的磷酸化与HBXIP结合活性的关系和相互作用结构域；揭示HBXIP作为辅激活因子上调PKCβII表达调控NMHC-IIA蛋白磷酸化增强纤维丝解聚的分子机制。本创新发现将为乳腺癌的防治和新药研发提供新的靶点。

The abnormality of protein post-translational modification is closely related to the occurrence and development of tumor. It has become a hot spot in international research to clarify its role and regulatory mechanism. Non-muscle myosin heavy chain IIA (NMHC-IIA) is highly expressed in tumors, and its filament polymerization and depolymerization affect the movement of tumor cells. However, the molecular mechanism modulating NMHC-IIA overexpression and filament changes in the promotion of tumors has not been clarified. In the preliminary work of this application, NMHC-IIA was significantly over-expressed in breast cancer metastasis tissues, and the expression levels of NMHC-IIA were negatively correlated with the patient survival. We also found that the interaction of HBXIP with NMHC-IIA induced the depolymerization of NMHC-IIA and the formation of cell plate pseudopods. In this application, breast cancer is taken as the research object, and the following research is carried out from the aspects of molecule, cell, human clinical tissue and animal model: to determine the role of HBXIP in up-regulating NMHC-IIA expression in breast cancer and its associated mechanism; to clarify the relationship between NMHC-IIA phosphorylation and its binding activity with HBXIP and their interaction domains; to reveal the molecular mechanism of HBXIP as a coactivator up-regulating PKCβII expression to induce NMHC-IIA protein phosphorylation for the enhancement of filament depolymerization. The innovative discovery will provide new targets for the prevention and treatment of breast cancer and new drug discovery.