Ma Pei, Zhang Meiling, Nie Fengqi, Huang Zebo, He Jing, Li Wei, Han Liang
Department of Oncology, First Affiliated Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
Department of Oncology, Second Affiliated Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
Biomed Pharmacother. 2017 Mar;87:20-26. doi: 10.1016/j.biopha.2016.12.079. Epub 2016 Dec 29.
The non-small cell lung cancer (NSCLC) patients harbor mutations in the epidermal growth factor receptor (EGFR) can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib, and show improved progression-free survival. However, most of the patients who are initially responsive to EGFR TKIs with activating EGFR mutations eventually develop acquired resistance after long-term therapy, and are followed by disease progression. Recently, diverse mechanisms of acquired EGFR TKI resistance have been reported, but little is known about the role of long noncoding RNAs in EGFR TKIs resistance. To gain insight into the expression pattern and potential function of lncRNAs in NSCLC cells EGFR-TKI resistance, we analyzed expression patterns in EGFR-TKIs-resistant cell lines and compared it with their parental sensitive cell line by using gene profiling datasets from Gene Expression Omnibus (GEO). Then, the expression levels of five chose lncRNAs were validated in PC9-gefitinib resistant cells (PC9G) and sensitive cells by using real-time quantitative PCR (qPCR). Among of these five lncRNAs, CASC9 expression was upregulated in PC9G and knockdown of its expression could increase the sensitivity of PC9G cells to gefitinib, while EWAST1 (LINC00227) is downregulated in PC9G cells and overexpressed EWAST1 also lead to increased sensitivity of PC9G cells to gefitinib. As indicated by GO analysis, the CASC9 and EWAST1 co-expressed genes are involved in several important pathways including regulation of cell growth, regulation of cell apoptosis and Chromatin assembly. Taken together, dysregulated lncRNAs play critical roles in EGFR-TKIs resistant NSCLC cells and might be used as novel potential targets to reverse EGFR-TKI resistance for NSCLC patients.
表皮生长因子受体（EGFR）发生突变的非小细胞肺癌（NSCLC）患者可通过EGFR酪氨酸激酶抑制剂（EGFR-TKI）进行靶向治疗，如吉非替尼，患者的无进展生存期得到改善。然而，大多数最初对具有激活EGFR突变的EGFR-TKIs有反应的患者在长期治疗后最终会产生获得性耐药，并随之出现疾病进展。最近，已有多种获得性EGFR-TKI耐药机制的报道，但关于长链非编码RNA在EGFR-TKIs耐药中的作用知之甚少。为了深入了解长链非编码RNA在NSCLC细胞EGFR-TKI耐药中的表达模式和潜在功能，我们通过使用来自基因表达综合数据库（GEO）的基因谱数据集，分析了EGFR-TKIs耐药细胞系中的表达模式，并将其与其亲本敏感细胞系进行比较。然后，通过实时定量PCR（qPCR）验证了五个选定的长链非编码RNA在PC9-吉非替尼耐药细胞（PC9G）和敏感细胞中的表达水平。在这五个长链非编码RNA中，CASC9在PC9G中的表达上调，敲低其表达可增加PC9G细胞对吉非替尼的敏感性，而EWAST1（LINC00227）在PC9G细胞中表达下调，过表达EWAST1也可导致PC9G细胞对吉非替尼的敏感性增加。基因本体（GO）分析表明，CASC9和EWAST1的共表达基因参与了包括细胞生长调控、细胞凋亡调控和染色质组装在内的几个重要途径。综上所述，失调的长链非编码RNA在EGFR-TKIs耐药的NSCLC细胞中起关键作用，可能作为逆转NSCLC患者EGFR-TKI耐药的新型潜在靶点。
