MiR-885影响肺腺癌预后及放射敏感性的作用机制研究

Lung adenocarcinoma (LAD) is considered to be a highly aggressive disease with great heterogeneity. However, rigorous biological markers for the predictions of prognosis and radiosensitivity are not well-defined and the molecular mechanisms underlying tumor progression remain elusive. We have performed microRNA (miRNA) microarray in stage IIIA LAD with radical surgery and found miR-885 to be a prognosis and radiosensitivity related miRNA. miR-885 expression downregulation was significantly associated with unfavorable prognosis including overall survival, disease free survival, and tumor control rate in LAD. In the subgroup analysis, downregulation of miR-885 was correlated with poor local regional tumor control rate in patients receiving postoperative radiotherapy. In this study, we will identify whether loss of miR-885 expression was mediated by DNA hypermethylation or genome mutations. Functional analyses of miR-885 affecting cell proliferation、cell circle、apoptosis、migration/invasion of LAD both in vivo and in vitro will be preformed. The identification of miR-885 target genes as well as the effects of miR-885 on radiosensitivity will also be focused. Finally, we will evaluate expression level of miR-885 in patients' plasma and try to find miR-885's correlation with clinical outcomes such as survival and tumor control. In summary, our proposed study will define whether miR-885 could represent a promising biomarker for prediction of prognosis and radiosensitivity as well as a potential therapeutic target for LAD, delivering more evidence for individualized clinical medical care.

肺腺癌具有侵袭性强、异质性大的特点，目前缺乏可靠的预后及放射敏感性生物标志物，并且肺腺癌发生发展的机制尚未被阐明。我们前期对接受根治性手术的IIIA期肺腺癌患者进行了microRNA（miRNA）表达谱研究，发现了miR-885低表达患者的总生存、无病生存和肿瘤控制率均显著降低。我们进一步对术后接受胸部放疗的肺腺癌患者进行亚组分析，结果显示miR-885低表达的患者其肿瘤局部区域控制率显著降低。本课题拟在上述基础上，针对miR-885与肺腺癌预后及放射敏感性的相关性，分别进行体内和体外实验阐释其对肺腺癌发生发展的影响；鉴定其在肺腺癌中下调的原因、靶基因及下游信号通路；明确其是否影响肿瘤的放射敏感性；分析其血浆中的水平与生存、肿瘤复发风险的关系。本研究将系统评价miR-885的预后及放射敏感性预测价值及其作为治疗新靶点的可能性，为临床个体化治疗提供重要理论和实验依据。

肺癌病死率居各种恶性肿瘤之首。其中肺腺癌占非小细胞肺癌的50%，具有侵袭性强、异质性大的特点，目前缺乏可靠的预后及放射敏感性生物标志物，并且肺腺癌发生发展的机制尚未被阐明。miRNAs在疾病预后评价、放射敏感性预测及靶向治疗方面具有光明的前景。生物信息学分析显示与正常组织相比，肿瘤组织中miR-4306高表达，而且生存分析提示miR-4306高表达是预后不良因素。本研究希望能够系统全面阐明miR-4306促癌及导致影响放疗敏感性的分子生物学机制。本研究通过上调和下调miR-4306基因的表达，在细胞系和动物模型层面发现miR-4306促进肿瘤增殖，侵袭以及放疗抵抗。利用生物信息学和双荧光素酶检测系统验证miR-4306的靶基因为IGF2R，在细胞层次验证了IGF2R过表达能够减弱miR-4306促进肿瘤细胞增殖侵袭和放疗抵抗的作用。在患者FFPE标本中miR-4306与IGF2R的表达具有显著相关性。此研究证实miR-4306通过靶向IGF2R显著影响肺腺癌的进展和对放疗的敏感性，miR-4306有望成为肺腺癌预后及放疗敏感性的分子标志物和有价值的药物作用靶点。