LncRNA/miRNA-34a调控AXL致肺癌靶向治疗继发耐药的机制研究

Lung cancer is one of the most common and devastating malignant disease worldwide. In previous work, we demonstrated that increased expression and activation of AXL caused resistance against EGFR-targeted therapy for lung cancer (Nature Genetics, 2012). However, the molecular mechanisms underlying regulation of AXL overexpression are unclear now. Our preliminary work found that an important miRNA-34a that regulates AXL expression was significantly down-regulated in EGFT-TKI resistant cells. By performing high throughput LncRNA sequencing analysis, we identified two LncRNAs as targets that may closely related to the physical interaction with miRNA-34a. Therefore, we hypothesize that these two.LncRNAs may regulate increased AXL expression through negatively regulating the function of the miRNA-34a in a subset of lung cancer. In current study, we will utilize EGFR-TKI sensitive/resistant lung cancer cell models that we originally established before, nude mouse transplantation tumor models, and clinical tissue samples pre- and post- resistance to EGFR-TKI in lung cancer patients to investigate the interaction of LncRNA with miRNA-34a and their roles on modulating AXL expression by using molecular/cellular approaches. We expect to discover certain LncRNAs as novel therapeutic targets for treatment of lung cancer.

肺癌是全球范围内最常见最致死的恶性肿瘤之一。最近我们在研究肺癌EGFR 靶向治疗获得性耐药的机制时发现 AXL 高表达并激活是肺癌 EGFR-TKI 耐药的一个重要新机制，但调控AXL表达增高的分子机制尚不明确。我们前期研究发现调节AXL的miRNA-34a在ER3耐药细胞中表达下调；LncRNA测序筛选出2个与miRNA-34a密切相关的LncRNA可能调节AXL的表达。因此我们假设LncRNA可能通过负性调节miRNA-34a从而进一步调控AXL高表达而导致肺癌细胞对EGFR-TKI耐药。本项目我们将通过肺癌细胞及动物模型和临床组织标本，采用CRISPR/Cas9等基因敲除/过表达技术系统全面探讨目标LncRNA与miRNA-34a的相互作用并调控AXL表达的分子机制，期望揭示LncRNA作为新的肺癌调节分子和关键的治疗靶标，为临床肺癌分子分型和个体化精准靶向治疗提供理论和实验依据。

在经费下达后，根据研究计划及实际研究调整，基本按时完成了项目的主要内容，发表的相关的研究论文。研究工作集中在：1）LncRNA/miRNA-34a调控AXL致肺癌靶向治疗继发耐药的机制研究；2) AXL-GAS6表达与非小细胞肺癌伴发脑转移的预后关系的研究；3）LncRNA XIST通过调节miR-101/EZH2促进食管鳞状细胞癌的恶化研究；4）受DNA损伤激活的非编码RNA的表达与食管鳞状细胞癌的不良预后相关研究；5）烟酰胺核苷通过激活SirT1/PGC-1α线粒体生物合成通路减轻酒精诱导的肝损伤；6）PDGF介导的间充质转化致使胶质母细胞瘤内皮细胞抵抗VEGF治疗；7）Brusatol在鼻咽癌中通过抑制Akt / mTOR信号通路发挥抗肿瘤作用；8）靶向间皮素的嵌合抗原受体NK-92细胞在卵巢癌中的应用。