Glaß Markus, Misiak Danny, Bley Nadine, Müller Simon, Hagemann Sven, Busch Bianca, Rausch Alexander, Hüttelmaier Stefan
Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany.
Front Mol Biosci. 2021 Mar 22;8:632219. doi: 10.3389/fmolb.2021.632219. eCollection 2021.
The oncofetal IGF2 mRNA-binding protein 1 (IGF2BP1) promotes tumor progression in a variety of solid tumors and its expression is associated with adverse prognosis. The main role proposed for IGF2BP1 in cancer cells is the stabilization of mRNAs encoding pro-oncogenic factors. Several IGF2BP1-RNA association studies, however, revealed a plethora of putative IGF2BP1-RNA targets. Thus, at present the main conserved target RNAs and pathways controlled by IGF2BP1 in cancer remain elusive. In this study, we present a set of genes and cancer hallmark pathways showing a conserved pattern of deregulation in dependence of IGF2BP1 expression in cancer cell lines. By the integrative analysis of these findings with publicly available cancer transcriptome and IGF2BP1-RNA association data, we compiled a set of prime candidate target mRNAs. These analyses confirm a pivotal role of IGF2BP1 in controlling cancer cell cycle progression and reveal novel cancer hallmark pathways influenced by IGF2BP1. For three novel target mRNAs identified by these studies, namely AURKA, HDLBP and YWHAZ, we confirm IGF2BP1 mRNA stabilization. In sum our findings confirm and expand previous findings on the pivotal role of IGF2BP1 in promoting oncogenic gene expression by stabilizing target mRNAs in a mainly 3'UTR, mA-, miRNA-, and potentially AU-rich element dependent manner.
癌胚胰岛素样生长因子2信使核糖核酸结合蛋白1（IGF2BP1）在多种实体瘤中促进肿瘤进展，其表达与不良预后相关。IGF2BP1在癌细胞中的主要作用是稳定编码促癌因子的信使核糖核酸。然而，多项IGF2BP1与核糖核酸关联研究揭示了大量可能的IGF2BP1核糖核酸靶点。因此，目前IGF2BP1在癌症中控制的主要保守靶点核糖核酸和途径仍不清楚。在本研究中，我们展示了一组基因和癌症标志性途径，它们在癌细胞系中呈现出依赖IGF2BP1表达的保守失调模式。通过将这些发现与公开的癌症转录组和IGF2BP1核糖核酸关联数据进行综合分析，我们编制了一组主要候选靶信使核糖核酸。这些分析证实了IGF2BP1在控制癌细胞周期进程中的关键作用，并揭示了受IGF2BP1影响的新的癌症标志性途径。对于这些研究确定的三个新靶信使核糖核酸，即极光激酶A（AURKA）、高密度脂蛋白结合蛋白（HDLBP）和14-3-3ζ（YWHAZ），我们证实了IGF2BP1对信使核糖核酸的稳定作用。总之，我们的研究结果证实并扩展了先前关于IGF2BP1通过以主要依赖3'非翻译区、N6-甲基腺苷、微小核糖核酸以及潜在富含AU元件的方式稳定靶信使核糖核酸来促进致癌基因表达的关键作用的发现。
