非小细胞肺癌(non-small cell lung cancer, NSCLC)是肺癌的主要病理类型，已严重威胁人类健康。NSCLC现有治疗方法疗效不尽人意，亟待深入探究其发生发展分子机制，以改进治疗、提高患者生存率。我们已证明抗体偶联纳米药物在抗肿瘤基因治疗中疗效显著(发表于Nature communications)。近期我们发现，OTUD1在NSCLC中显著下调，并且导致患者生存预后差。进一步通过RNA测序分析，显示OTUD1调控TNF/NF-kB通路；通过免疫共沉淀-生物质谱分析，鉴定RIPK1和RAD23B为OTUD1相互作用蛋白。功能学实验表明OTUD1抑制NF-kB活性，促进程序性坏死(necroptosis)，抑制DNA损伤修复。本课题将承前启后，应用纳米载体药物深层次解析OTUD1抑制NSCLC的分子机制，并与临床相结合验证，为NSCLC提供新标志物、新治疗靶标和方法。

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer related death worldwide and in China. Non-small cell lung cancer (NSCLC) is the main histological type of lung cancer, which accounts for nearly 85% of all cases of lung cancer. The prognosis of NSCLC patients is extremely poor, with an estimated 5-year survival rate of less than 20%, due to the low response of current available therapeutics. NSCLC has become one of the most serious threat to human. It is urgent and important to study the pathological and molecular mechanisms that initiated the disease and promoted its progression in order to improve the treatment and outcome of patients...Previously, we reported that EGFR antibody-conjugated nanoparticle successfully delivered PBOV1 silencing plasmids to hepatocellular carcinoma (HCC) cells in vivo and in vitro for gene therapy. This nanomedicine showed great antitumor activity as it inhibited HCC proliferation, cancer stem cell population, invasion, metastasis and so on (Published in Nature Communications). Recently, we identified that OTUD1 was significantly downregulated in NSCLC and associated with poor survival rate. Then, we performed RNA sequencing in A549-vector and A549-OTUD1 overexpression cells. Gene ontology and KEGG pathway analysis revealed that OTUD1 took part in regulation of TNF/NE-kB signaling pathway. Next, by co-immunoprecipitaion and mass spectrum analysis, RIPK1 and RAD23B were identified as OTUD1-interacting proteins. Further investigation showed that OTUD1 inhibited the activity of NF-kB, promoted necroptosis and impaired DNA damage repair. All in all, these results indicated that OTUD1 is a tumor suppressor in NSCLC...In this project, we will deeply investigate the underlying molecular mechanisms of how OTUD1 inhibiting NSCLC and analyze the correlation between OTUD1 expression and clinical characteristics of patients and the clinical significance of OTUD1 in NSCLC. Moreover, we will employ the nanoparticle to develop an OTUD1-based nanomedicine and use it for treating NSCLC in vitro and in vivo. Thus, the findings of this study will provide us new targets and therapeutic strategy to improve the outcome of NSCLC patients, which is of great clinical significance.