Wnt通路关键基因DVL1的可变剪接在肺癌中的功能与机制研究

RNA可变剪接与信号转导通路在肿瘤发生发展中发挥重要作用，但是目前对它们之间的作用机制与功能联系的认识还非常有限。我们前期研究发现，在肺癌细胞中Wnt信号可调控其通路中关键基因DVL1的可变剪接；而DVL1可变剪接可控制Wnt信号通路的活性，并且改变DVL1磷酸化状态与相分离性质。本申请项目将在此基础上，深入研究DVL1可变剪接在肺癌发生发展中的功能，重点探究受可变剪接调控的DVL1磷酸化和相分离在Wnt信号通路中的功能与机制，并鉴定由DVL1可变剪接介导的Wnt通路正向反馈激活的作用途径。通过本项目的实施，我们期望揭示可变剪接在信号转导和相分离中的新功能以及这些重要细胞机制之间协调作用的新模式，发现肿瘤细胞中Wnt信号通路异常激活的新机制与作用途径，并可能为肺癌临床诊断和治疗提供新的潜在靶点和策略。

Both alternative RNA splicing and signal transduction play critical roles in cancer development and progression; however, our understanding of the actions and links between these two cellular processes remains elusive. Our preliminary results showed that Wnt signal regulates the alternative splicing of its key component, DVL1, in lung cancer cells; whereas DVL1 splicing is also able to control the activity of Wnt signaling, as well as the phosphorylation state and liquid-like property of DVL1. Based on these data, we will investigate the roles of DVL1 alternative splicing in lung cancer development and progression, characterize the mechanisms and functions for the splicing-regulated phosphorylation and phase separation of DVL1 in Wnt signaling cascade, and identify the positive feed-forward loop of Wnt activation mediated by DVL1 splicing. Taken together, we aim to reveal new functions of alternative splicing in signal transduction and phase condensation and new mode of cellular integration of these key mechanisms, unravel new mechanism and pathway of aberrant activation of Wnt signaling in cancer, and provide novel potential targets and strategies for the diagnosis and treatment of lung cancer.