lncRNA HOTAIR介导的Wnt/β-catenin与EGFR信号通路对话调控肺腺癌侵袭的机制研究

EGFR酪氨酸激酶抑制剂（EGFR-TKIs）继发性耐药是制约肺腺癌EGFR-TKIs靶向治疗的瓶颈。ADAM17在EGFR配体胞外域脱落中起着重要作用，但目前仍缺乏ADAM17在肺腺癌靶向治疗中的作用研究。Wnt信号与EGFR信号通路存在交汇对话,共同参与调控肿瘤侵袭过程。HOTAIR是第一个被发现具有反式转录调控作用的长非编码RNA（lncRNA),可通过Wnt/β-Catenin信号通路调控食管癌进展。但其参与调控肺腺癌侵袭的作用和机制仍有待于研究。我们已发现A549细胞中EGFR磷酸化水平升高，慢病毒介导的ADAM17 RNAi可抑制其表达。为此，本项目将研究lncRNA HOTAIR介导的Wnt/β-catenin与EGFR信号通路对话调控肺腺癌侵袭过程的作用机制及慢病毒介导的ADAM17 RNAi能否逆转肺腺癌EGFR-TKIs耐药，为治疗肺腺癌EGFR-TKI耐药提供新靶点。

Secondary resistance of EGFR tyrosine kinase inhibitors (EGFR-TKIs) is a bottleneck in EGFR-TKIs targeted therapy of lung cancer. ADAM17 plays an important role in shedding of extracellular domain of EGFR ligand, but its role in targeted therapy of lung cancer is still needed to be studied. Intersection between Wnt signal and EGFR signaling pathway participates in the regulation of tumor invasion. HOTAIR is a long non-coding RNA (lncRNA), first to be discovered to have function of trans-transcriptional regulation, which may regulate development of esophageal cancer through Wnt/β-Catenin signal pathway. However, its involvement in regulation of lung adenocarcinoma invasion remains to be studied. We have found that EGFR phosphorylation was increased in A549 cells, lentivirus mediated ADAM17 RNAi could significantly inhibit the expression. Thus, in the present study, we will explore the regulatory mechanism of lncRNA HOTAIR mediated Wnt/β-catenin and EGFR signal pathway in lung adenocarcinoma invasivsion in vitro and in vivo and whether lentivirus mediated ADAM17 RNAi can reverse the secondary resistance of lung adenocarcinoma to EGFR-TKI, which could provide a new strategy to solve the secondary drug resistance of lung adenocarcinoma to EGFR-TKI.