We performed an integrative transcriptomic in silico analysis using lung adenocarcinoma A549 cells treated with the neddylation inhibitor MLN4924 and the gefitinib-resistant PC9 cell line (PC9GR). We focused on the transcriptional effects of the top differentially expressed ncRNA biotypes and their correlating stemness factors. Interestingly, MLN4924-treated cells showed a significant upregulation of mRNAs involved in carcinogenesis, cell attachment, and differentiation pathways, as well as a parallel downregulation of stemness maintenance and survival signaling pathways, an effect that was inversely observed in PC9GR cells. Moreover, we found that stemness factor expression could be contrasted by selected up-regulated ncRNAs upon MLN4924 treatment in a dose and time-independent manner. Furthermore, upregulated miRNAs and lncRNA-targeted mRNAs showed an evident enrichment of proliferation, differentiation, and apoptosis pathways, while downregulated ncRNA-targeted mRNAs were implicated in stem cell maintenance. Finally, our results proved that stemness (KLF4andFGFR2) and epithelial–mesenchymal transition (ZEB2,TWIST2,SNAI2,CDH2, andVIM) factors, which are highly expressed in PC9GR cells compared to gefitinib-sensitive PC9 cells, could be abrogated with the neddylation inhibitor MLN4924 mainly through activation of epithelial differentiation pathways, thus exerting a protective role in lung cancer cells and chemosensitivity against lung tumorigenic transformation.
我们采用整合转录组学方法，对经去泛素化抑制剂MLN4924处理的肺腺癌A549细胞及吉非替尼耐药PC9细胞系（PC9GR）进行了计算机模拟分析。研究重点关注差异表达最显著的非编码RNA生物型及其相关干性因子的转录调控效应。值得注意的是，MLN4924处理组细胞中涉及致癌过程、细胞黏附与分化通路的mRNA显著上调，同时干性维持与生存信号通路呈现平行下调，而PC9GR细胞中观察到完全相反的调控模式。进一步研究发现，MLN4924处理可通过特定上调的非编码RNA以剂量和时间非依赖方式拮抗干性因子表达。机制层面，上调的miRNA和lncRNA靶向mRNA在增殖、分化及凋亡通路中显著富集，而下调的非编码RNA靶向mRNA主要参与干细胞维持功能。最终研究证实：相较于吉非替尼敏感型PC9细胞，PC9GR细胞中高表达的干性因子（KLF4与FGFR2）及上皮-间质转化因子（ZEB2、TWIST2、SNAI2、CDH2和VIM）可被MLN4924通过激活上皮分化通路有效抑制，从而在肺癌细胞中发挥保护作用并增强对肺肿瘤转化的化学敏感性。
ncRNAs Orchestrate Chemosensitivity Induction by Neddylation Blockades
肿瘤(癌症)患者之家