RNA解旋酶DDX3X调控Kras翻译促进肺癌进程和引发肺癌性别差异的作用机制研究

肺癌是世界范围内发病率和死亡率最高的恶性肿瘤。尽管已有靶向肺癌关键驱动基因KRAS的小分子药物进入临床实验，但研究显示肺癌细胞可以快速形成对该类药物的耐药性，因此如何长期有效抑制KRAS仍是目前肺癌研究领域的一个难点。本研究运用小鼠自发性肺癌模型，初步证实了靶向定位于X染色体上的RNA解旋酶DDX3X可在翻译水平显著抑制KRAS的表达，从而大大延缓肺癌的进程；且DDX3X定位于可以逃逸X染色体失活的区域，导致其表达水平存在显著性别差异，因而可能是引发肺癌性别差异的遗传因素。本研究将详细阐述DDX3X如何实现对KRAS的翻译调控以及其他潜在的调控肺癌进程的机制，揭示其同源基因DDX3Y与DDX3X的功能差异以及在DDX3X被抑制时DDX3Y如何起到代偿作用；同时探索运用基因编辑技术通过靶向DDX3X实现翻译水平抑制KRAS。本研究将为治疗KRAS突变驱动的肺癌提供新的治疗靶点和治疗策略。

Lung cancer is the most prevalent and the leading cause of cancer-related death worldwide. Currently, targeting "undruggable target" Kras is a big challenge in the lung cancer research field, although some small molecular drugs targeting KRAS specifically have been tested in the clinical trial, the rapid adaption of cancer cells and associated drug resistance to these drugs have been already reported. Here, using a classical murine spontaneous lung cancer model, we identify the RNA helicase DDX3X is a key regulator of lung cancer progression by regulating oncogenic Kras translation. DDX3X is located on the X chromosome which can escape from X chromosome inactivation, resulting a significant dosage difference between female and male, thus contributing to lung cancer gender bias genetically. We aim to explore the detail mechanisms of how DDX3X regulates Kras translation as well as other potential mechanisms involved in lung cancer progression, moreover, we seek to uncover the difference between DDX3X and its homologue DDX3Y, and how DDX3Y compensates the loss of function of DDX3X in the context of lung cancer. Finally, with well-established gene editing technology, we intend to investigate whether targeting DDX3X is an effective method to inhibit Kras expression and thereby shed light on novel targets and strategies for Kras driven lung cancer therapy.