预测非小细胞肺癌淋巴结转移miRNAsPanel的建立及其功能和分子机制探讨

Lymphatic metastasis is significantly associated with nonsmall cell lung cancer prognosis. Accurate prediction of lymphatic metastasis status helps to the personalized therapy of patients. Combination of mutiple miRNAs expression levels in tumor tissue or circulating blood maybe helpful in tumor diagnosis and prognosis of nonsmall cell lung cancer, however, the related studies in lymphatic metastasis of lung cancer were rare and especially, miRNAs panel for diagnosing lymphatic metastasis of lung cancer was lack. In our previous work, we identified 15 candidate miRNAs by profiling miRNAs in lung cancer lymph nodes and analysis of public available data. The preliminary results suggested the diagnosis accuracy of risk model constructed by the candidate miRNAs in lymphatic metastasis was high, however, this need to be validated in large scale samples. In this project, we aim to collect a large number of tissue and peripheral blood samples of lung cancer to verify the candidate miRNAs. Then cell experiments, chicken embryo allantois membrane model, and mice xenograft tumor model will be performed to study the biological functions of the candidate miRNAs, miRNAs targets, and downstream cell signaling pathway. Furthermore, the therapeutic effects of the candidate miRNAs as a candidate drugs in lung cancer will be evaluated in lung cancer patient-derived xenograft model.

淋巴转移与非小细胞肺癌预后关系密切，准确判断淋巴转移状态有助于患者个体化治疗。肿瘤组织及循环血中多个miRNAs联合检测在淋巴转移预测方面的相关研究较少，尤其缺乏非小细胞肺癌淋巴转移的特征性miRNAs表达谱（miRNAs Panel）的相关报道。前期工作中，我们通过对有肺癌转移淋巴结中miRNAs表达谱的检测和公共数据的分析，筛选到15个候选miRNAs，初步研究表明，由这些miRNAs构建的风险模型对肺癌淋巴转移的预测准确度达到79.2%，但需在大样本中进行验证和模型修正。本项目将收集300例非小细胞肺癌组织和外周血样本验证候选miRNAs的预测价值；通过细胞功能实验，包括鸡胚尿囊膜模型、小鼠移植瘤模型等分析鉴定候选miRNAs的生物学功能，同时探索候选miRNAs调控的下游靶基因及细胞信号通路；通过人源肺癌移植瘤模型（PDX）评价候选miRN作为候选药物抑制肺癌生长和转移的价值。

淋巴转移与非小细胞肺癌预后关系密切，准确判断淋巴转移状态有助于患者个体化治疗。肿瘤组织及循环血中多个miRNAs联合检测在淋巴转移预测方面的相关研究较少，尤其缺乏非小细胞肺癌淋巴转移的特征性miRNAs表达谱（miRNAs Panel）的相关报道。前期工作中，我们通过对有肺癌转移淋巴结中miRNAs表达谱的检测和公共数据的分析，筛选到15个候选miRNAs，初步研究表明，由这些miRNAs构建的风险模型对肺癌淋巴转移的预测准确度达到79.2%。其中miR-224在有淋巴结转移的组织样本中表达明显升高，本项目miR-224进行深入研究，通过细胞功能实验，鸡胚尿囊膜模型等分析鉴定了miR-224在肺癌中发挥癌基因的作用，同时探索miR-224调控的下游靶基因；通过本研究明确了miR-224通过直接靶向肿瘤抑制因子血管生成素样蛋白(ANGPTL)促进非小细胞肺癌细胞恶性表型的作用及分子机制，miR-224有望成为预测非小细胞肺癌淋巴结转移的潜在生物标志物。