DataSheet2_Analysis of the lncRNA–miRNA–mRNA Network Reveals a Potential Regulatory Mechanism of EGFR-TKI Resistance in NSCLC.PDF

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are widely used for patients with EGFR-mutated lung cancer. Despite its initial therapeutic efficacy, most patients eventually develop drug resistance, which leads to a poor prognosis in lung cancer patients. Previous investigations have proved that non-coding RNAs including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs) contribute to drug resistance by various biological functions, whereas how they regulate EGFR-TKI resistance remains unclear. In this study, we examined gene expression using the microarray technology on gefitinib-resistant NSCLC cells to obtain differentially expressed (DE) lncRNAs and mRNAs. A total of 45 DE-lncRNAs associated with overall survival and 1799 target DE-mRNAs were employed to construct a core lncRNA–miRNA–mRNA network to illustrate underlying molecular mechanisms of how EGFR-TKI resistance occurs in NSCLC. We found that target DE-mRNAs were mainly enriched in pathways involved in EGFR-TKI resistance, especially the target DE-mRNAs regulated by LINC01128 were significantly enriched in the PI3K/Akt signaling pathway, where the synergy of these target DE-mRNAs may play a key role in EGFR-TKI resistance. In addition, downregulated LINC01128, acting as a specific miRNA sponge, decreases PTEN via sponging miR-25-3p. Furthermore, signaling reactions caused by the downregulation of PTEN would activate the PI3K/Akt signaling pathway, which may lead to EGFR-TKI resistance. In addition, a survival analysis indicated the low expression of LINC01128, and PTEN is closely related to poor prognosis in lung adenocarcinoma (LUAD). Therefore, the LINC01128/miR-25-3p/PTEN axis may promote EGFR-TKI resistance via the PI3K/Akt signaling pathway, which provides new insights into the underlying molecular mechanisms of drug resistance to EGFR-TKIs in NSCLC. In addition, our study sheds light on developing novel therapeutic approaches to overcome EGFR-TKI resistance in NSCLC.

表皮生长因子受体酪氨酸激酶抑制剂（Epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs）被广泛应用于携带EGFR突变的肺癌患者。尽管其初始治疗疗效显著，但大多数患者最终会产生耐药性，进而导致肺癌患者预后不良。既往研究证实，包括长链非编码RNA（long non-coding RNAs, lncRNAs）、环状RNA（circular RNAs, circRNAs）和微小RNA（microRNAs, miRNAs）在内的非编码RNA，可通过多种生物学功能参与耐药进程，但它们调控EGFR-TKI耐药的具体分子机制仍未明确。本研究采用微阵列技术检测吉非替尼耐药非小细胞肺癌（non-small cell lung cancer, NSCLC）细胞的基因表达谱，以筛选差异表达（differentially expressed, DE）的lncRNAs与mRNA。我们共纳入45个与总生存期相关的差异表达lncRNAs以及1799个靶标差异表达mRNA，构建核心lncRNA–miRNA–mRNA调控网络，以阐明非小细胞肺癌中EGFR-TKI耐药的潜在分子机制。研究发现，靶标差异表达mRNA主要富集于与EGFR-TKI耐药相关的信号通路，其中受LINC01128调控的靶标差异表达mRNA显著富集于PI3K/Akt信号通路，此类靶标mRNA的协同作用可能在EGFR-TKI耐药过程中发挥关键作用。此外，低表达的LINC01128可作为特异性miRNA海绵，通过吸附miR-25-3p下调PTEN的表达水平。进一步研究显示，PTEN下调所介导的信号级联反应可激活PI3K/Akt信号通路，进而可能诱发EGFR-TKI耐药。生存分析结果表明，LINC01128与PTEN的低表达与肺腺癌（lung adenocarcinoma, LUAD）患者的不良预后密切相关。综上，LINC01128/miR-25-3p/PTEN调控轴可能通过PI3K/Akt信号通路促进非小细胞肺癌的EGFR-TKI耐药，这为阐明非小细胞肺癌中EGFR-TKI耐药的潜在分子机制提供了新的研究视角，同时也为开发克服EGFR-TKI耐药的新型治疗策略提供了理论依据。