C19orf12促进非小细胞肺癌细胞EMT与转移的机制研究

The discovery of new cancer related genes is of great significance for the treatment of cancer. Our research group has been focused on the epithelial mesenchymal transition (EMT) and the molecular mechanisms of metastasis. Our previous studies showed that C19orf12, which has never been reported in cancer, has high level expression in non small cell lung cancer (NSCLC) through bioinformatics and clinical analysis. In addition, alteration of C19orf12 expression has a great impact on migration in vitro and metastasis in vivo of A549 cells. Futhermore, expression levels of EMT markers, E-cadherin and ZO-1, were also significantly altered. We also found that C19orf12 interacts with NEMO, a NF-κB pathway upstream regulator. Therefore, the objective of this project is to systematically explore the function and regulatory mechanisms of C19orf12 in EMT and NSCLC metastasis at in vitro and in vivo levels as well as clinical cases. Specifically, we will also dissect the manner of interaction between NEMO and C19orf12 and its effect on NF-κB pathway activation, and further confirm if C19orf12's impact on the EMT and NSCLC metastasis is dependent on interaction with NEMO. The project will expand our understanding of the process of NSCLC metastasis and will provide a molecular theoretical basis for NF-κB pathway targeting therapy in lung cancer.

发现新的癌相关基因对癌症的治疗具有重要意义。本课题组一直从事上皮间质转化（EMT）与癌症转移的机制研究。前期利用生物信息学分析与临床样本验证，我们发现了一个从未在癌症中报道的基因C19orf12高表达于非小细胞肺癌（NSCLC）。人为改变C19orf12表达丰度可以影响A549细胞的体外迁移与体内转移能力，EMT标志分子E-cadherin与ZO-1表达亦发生显著改变。此外，我们还发现C19orf12与NF-κB通路关键分子NEMO存在相互作用。故本课题拟在细胞与动物模型以及临床病例三方面系统阐述C19orf12在EMT与肺癌转移中的作用。同时我们拟进一步探索其与NEMO相互作用的形式及其对NF-κB通路活化的影响，并确认C19orf12是否通过NEMO相互作用而影响EMT与肺癌转移。课题的顺利进行将丰富对肺癌转移机制的认识，并为针对NF-κB通路的靶向治疗药物研发提供分子理论基础。

多项研究显示二甲双胍具有抗肿瘤作用，但是决定肿瘤对与二甲双胍敏感性的因素尚不清楚。本项研究我们发现C19orf12是一个潜在的二甲双胍治疗指标。我们发现C19orf12在非小细胞肺癌中表达上调，并且可以促进肿瘤细胞体外迁移及体内的转移。C19orf12通过抑制一群电子传递链基因的表达导致NAD+/NADH比值下降；增强肿瘤有氧糖酵解功能；促进谷氨酰胺还原羧化；增加细胞脂质不饱和度。更重要的是我们证明二甲双胍与C19orf12的高表达具有协同抗肿瘤作用。此外，我们还发现了3个miRNA可以抑制C19orf12的表达并且与二甲双胍敏感性负相关。