EPB41/c-Myc负反馈环路在非小细胞肺癌发生发展中的作用机制研究

Non-small cell lung cancer (NSCLC) is the most common cancer with the highest incidence and mortality worldwide. Identification of new NSCLC pathogenic genes are urgently needed. In our previous study, we developed an integrative functional genomics methodology to identify cancer susceptibility SNPs in transcription factor-binding sites across the whole genome. By using the new strategy, we identified EPB41 as a new tumor suppressor gene in hepatocellular carcinoma. However, the role of EPB41 in the development of NSCLC is still unclear. Our preliminary results showed that EPB41 was down-regulated in NSCLC tumor tissue and associated with tumor staging, pathological type or prognosis. And we also demonstrated that EPB41 could suppress the proliferation and epithelial-mesenchymal transition of NSCLC cells in vitro. All these results suggested that EPB41 might be a candidate tumor suppressor gene for NSCLC. Besides, we also discovered the EPB41/c-Myc negative feedback loop during NSCLC pathogenesis. Based on this hypothesis, the project will focus on the molecular mechanism and biological effect of EPB41/c-Myc negative feedback loop. The results of this study will initially explain how EPB41 is involved in development of NSCLC, which may not only extend our understanding on the molecular function of EPB41 in tumorgenesis, but also provide theoretical supports for discovery of early diagnostic markers and development of drugs targeting the EPB41/c-Myc feedback loop.

非小细胞肺癌（NSCLC）是发病率和死亡率较高的恶性肿瘤，发现、鉴定NSCLC全新致病基因对于阐明其发病机理意义重大。我们前期利用整合功能基因组学策略发现了全新抑癌基因EPB41，但其在NSCLC发生发展中的作用仍不清楚。为了揭示其功能，我们开展了一系列前期研究工作，结果显示：EPB41在NSCLC肿瘤组织中表达显著下调，且与患者不良预后等多项恶性临床症状显著负相关，提示其为重要的NSCLC抑癌基因；功能实验也证实EPB41可负向调控NSCLC细胞的增殖及EMT过程。在对其上游调控机制及所影响的下游信号通路的初步探索中，我们发现存在EPB41/c-Myc负反馈调节环路。基于此，本项目拟深入研究EPB41的上下游信号通路，揭示EPB41/c-Myc负反馈调节环路的分子机制及生物学效应。研究成果将为NSCLC发病机制的理解、早期诊断分子标志物的发现及相关药物的研发提供重要的理论支撑和实验依据。

非小细胞肺癌(NSCLC)是发病率和死亡率较高的恶性肿瘤，发现、鉴定NSCLC全新致病基因对于阐明其发病机理意义重大。我们前期利用整合功能基因组学策略发现了全新抑癌基因EPB41，但其在NSCLC发生发展中的作用仍不清楚。为了揭示其功能，我们开展了一系列前期研究工作，结果显示:EPB41在NSCLC肿瘤组织中表达显著下调，且与患者不良预后等多项恶性临床表型显著负相关，提示其为重要的NSCLC抑癌基因;功能实验也证实EPB41可负向调控NSCLC细胞的增殖、EMT过程、皮下成瘤及肺转移等。在对其下游信号通路的初步探索中，我们发现EPB41可与ALDOC结合并影响其功能进而激活Wnt信号通路并调控下游靶基因表达，具体来说EPB41可竞争性结合ALDOC，导致与β-Catenin降解复合物结合的ALDOC减少，并最终致使β-Catenin降解增多。研究成果将为NSCLC发病机制的理解、早期诊断分子标志物的发现及相关药物的研发提供重要的理论支撑和实验依据。