Zhang Nan, Song Gui-Yuan, Yu Qing-Hua, Fan Xin-Ming, Zhang Wen-Shuo, Hu Yong-Jian, Chao Tian-Zhu, Wu Yao-Yao, Duan Shu-Yan, Wang Fei, Du Rui-Peng, Xu Ping
Laboratory of Radiation-Induced Diseases and Molecule-Targeted Drugs, School of Food and Biomedicine, Zaozhuang University, Zaozhuang, Shandong, China.
School of Pharmacy, Weifang Medical University, Weifang, Shandong, China.
Front Pharmacol. 2024 Mar 6;15:1335374. doi: 10.3389/fphar.2024.1335374. eCollection 2024.
Previous studies have documented important roles for microRNA-147 (miR-147) in inflammation, radiation-induced injury, cancer, and a range of other diseases. Murine lungs exhibit high levels of miRNA, mRNA, and lncRNA expression. However, very little research to date has focused on the lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) networks associated with miR-147, and the regulation of lncRNAs and miRNAs in this setting remains poorly understood. After establishing a miR-147 model mouse, samples of lung tissue were harvested for RNA-sequencing, and differentially expressed lncRNAs, miRNAs, and mRNAs were identified. The miRNA targets of these lncRNAs and the identified miRNAs were first overlapped to facilitate the prediction of target mRNAs, with analyses then examining the overlap between these targets and mRNAs that were differentially expressed. Then, these target mRNAs were subjected to pathway enrichment analyses. These results were ultimately used to establish a miR-147-related ceRNA network. Relative to wild-type mice, the lungs of miR-147 mice exhibited 91, 43, and 71 significantly upregulated lncRNAs, miRNAs, and mRNAs, respectively, together with 114, 31, and 156 that were significantly downregulated. The lncRNA-miRNA-mRNA network established based on these results led to the identification of Kcnh6 as a differentially expressed hub gene candidate and enabled the identification of a range of regulatory relationships. KEGG pathway enrichment showed that the mRNA targets of differentially expressed lncRNAs and miRNAs in the mice were associated with tumor-related signaling, endometrial cancer, bladder cancer, and ErbB signaling. These results suggest that the identified ceRNA network in miR-147 mice shapes tumor-associated signaling activity, with miR-147 potentially regulating various lncRNAs and miRNAs through Kcnh6, ultimately influencing tumorigenesis. Future studies of the lncRNA, miRNA, and mRNA regulatory targets shown to be associated with miR-147 in the present study may ultimately lead to the identification of novel clinically relevant targets through which miR-147 shapes the pathogenesis of cancer and other diseases.
先前的研究已证明微小RNA - 147（miR - 147）在炎症、辐射诱导损伤、癌症及一系列其他疾病中发挥重要作用。小鼠肺部呈现出高水平的微小RNA、信使核糖核酸（mRNA）和长链非编码核糖核酸（lncRNA）表达。然而，迄今为止，很少有研究聚焦于与miR - 147相关的lncRNA - miRNA - mRNA竞争性内源RNA（ceRNA）网络，且在这种情况下lncRNA和miRNA的调控仍知之甚少。建立miR - 147模型小鼠后，采集肺组织样本进行RNA测序，鉴定出差异表达的lncRNA、miRNA和mRNA。首先将这些lncRNA的miRNA靶标与鉴定出的miRNA进行重叠，以促进靶标mRNA的预测，随后分析这些靶标与差异表达的mRNA之间的重叠情况。然后，对这些靶标mRNA进行通路富集分析。这些结果最终用于建立与miR - 147相关的ceRNA网络。相对于野生型小鼠，miR - 147小鼠的肺部分别有91个、43个和71个lncRNA、miRNA和mRNA显著上调，同时有114个、31个和156个显著下调。基于这些结果建立的lncRNA - miRNA - mRNA网络导致鉴定出Kcnh6作为差异表达的枢纽基因候选物，并确定了一系列调控关系。京都基因与基因组百科全书（KEGG）通路富集显示，小鼠中差异表达的lncRNA和miRNA的mRNA靶标与肿瘤相关信号传导、子宫内膜癌、膀胱癌和表皮生长因子受体（ErbB）信号传导相关。这些结果表明，在miR - 147小鼠中鉴定出的ceRNA网络塑造了肿瘤相关信号传导活性，miR - 147可能通过Kcnh6调控各种lncRNA和miRNA，最终影响肿瘤发生。本研究中显示与miR - 147相关的lncRNA、miRNA和mRNA调控靶标的未来研究，最终可能导致鉴定出新的临床相关靶标，通过这些靶标miR - 147塑造癌症和其他疾病的发病机制。
