低氧诱导的miR-196a/miR-218表达异常在非小细胞肺癌EGFR-TKI耐药 中的作用及机制研究

EGFR-TKI耐药是肺癌治疗的难点且机制仍不完全清楚。我们前期研究发现：低氧与肺癌EGFR-TKI耐药相关，低氧处理后肺癌细胞中miR-196a明显上调，miR-218明显下调，miR-196a和miR-218启动子区分别存在HIF-1α/SP1、HIF-1α/C-MYC结合位点和表观遗传修饰区域。miR-196a可能靶向XAF1和WIF-1，miR-218可能靶向ABCG2和P70S6K1。因此我们推测：低氧环境下，HIF-1α与SP1/P300和C-MYC/DNMT结合通过表观遗传方式转录调控miR-196a和miR-218的表达，进而调控凋亡、EMT、血管生成等信号通路导致肺癌EGFR-TKI耐药。本项目拟从临床、细胞、动物三方面阐明低氧诱导的miRNA-196a/miRNA-218表达异常在EGFR-TKI耐药中的作用及机制。项目的完成将丰富对肺癌EGFR-TKI耐药机制的认识。

EGFR-TKI drug resistance is the difficulty of drug treatment of non-small cell lung cancer and the mechanism is not entirely clear. Our preliminary study found that hypoxia was associated with EGFR-TKI resistance in lung cancer patients, miR-196a was significantly up-regulated and miR-218 was down-regulated and in lung cancer cells after hypoxia treatment, the promoter region of miR-196a and miR-218 had epigenetic modification, which may be regulated by HIF-1α/SP1 and HIF-1α/C-MYC . Furthermore, miR-196a may target XAF1 and WIF-1. MiR-218 may target ABCG2 and P70S6K1.Therefore, we propose a hypothesis that HIF-1α may recruit SP1/P300 and C-MYC/DNMT to regulate the abnormal expression of miR-196a and miR-218 through transcriptional activation and epigenetic modification and then regulate apoptosis, EMT, angiogenesis and other signaling pathways leading to lung cancer EGFR-TKI resistant.The aim of the present study was to elucidate the role of hypoxia-induced miRNA-196a / miRNA-218 expression in EGFR-TKI resistance from clinical, cellular to animal. The completion of the project will enrich the understanding of lung cancer EGFR-TKI resistance mechanism.