WWP2通过Beclin1介导的自噬促进肺癌发生发展的机制研究

肺癌发病率和死亡率均居我国各类肿瘤首位，但其发病机制尚未阐明。我们前期研究发现WWP2在肺癌组织和细胞系中高表达，且与肺癌患者不良预后密切相关。利用shRNA转染稳定沉默WWP2的表达抑制肺癌细胞增殖、阻滞细胞周期、增加细胞凋亡、阻断EMT。敲低WWP2的表达还抑制肺癌细胞自噬活性，同时降低调控自噬活化的关键因子Beclin1的表达，WWP2还参与调控血清饥饿诱导的自噬，促进肺癌细胞存活。因此我们推测：WWP2可能通过Beclin1介导的自噬促进肺癌发生发展。我们拟利用细胞和裸鼠模型以及临床标本研究WWP2促进肺癌发生发展的机制，重点研究WWP2调节Beclin1表达进而调控自噬活性及其在肺癌发生发展中的作用和机制。本研究从分子、细胞、动物模型和临床标本多角度探讨WWP2通过Beclin1调控自噬的分子机制及其在肺癌发生发展中的作用，有望丰富自噬调控机制，为肺癌诊断和靶向治疗奠定理论基础。

While the incidence and mortality of lung cancer rank the first in all cancers in China, the pathogenesis mechanism of lung cancer has not been elucidated. Our previous study found that WWP2 was highly expressed in lung cancer tissues and cell lines, and was closely related to the poor prognosis of lung cancer patients. Stably silence WWP2 expression by shRNA inhibited lung cancer cell proliferation, arrested cell cycle, increased apoptosis, and blocked EMT. Knockdown of WWP2 expression also inhibited autophagy in lung cancer cells with association of reduced expression of the key autophagy factor Beclin1. WWP2 was also involved in the regulation of serum-starvation-induced autophagy and lung cancer cell survival. Therefore, we hypothesize that WWP2 promotes lung cancer development through Beclin1-mediated autophagy. By using cell culture, nude mouse models and clinical specimens, we will study the role and mechanism of WWP2 in promoting the development of lung cancer, focusing on the how WWP2 regulates autophagy in lung cancer. This study will elucidate the molecular mechanism by which WWP2 promotes lung cancer development and lay a theoretical foundation for the diagnosis and targeted therapy of lung cancer.