Mesenchymal glioblastoma constitutes a major ceRNA signature in the TGF-β pathway.
Mesenchymal glioblastoma constitutes a major ceRNA signature in the TGF-β pathway.
复制标题
间充质胶质母细胞瘤构成 TGF-β 途径中的主要 ceRNA 特征
作者：
Wang Q;Cai J;Fang C;Yang C;Zhou J;Tan Y;Wang Y;Li Y;Meng X;Zhao K;Yi K;Zhang S;Zhang J;Jiang C;Zhang J;Kang C
理由：竞争性内源 RNA (ceRNA) 网络在转录后调控中发挥重要作用。它们的失调在癌症中很常见。然而，在间充质胶质母细胞瘤 (GBM) 的侵袭性和侵袭性表型中，ceRNA 特征的研究很少。本研究旨在在 mRNA-miRNA 水平上表征间充质胶质母细胞瘤，并鉴定 ceRNA 网络 (micNET) 标记中的 mRNA 及其在肿瘤发生中的机制。方法：通过构建 GBM ceRNA 网络，然后与 STRING 蛋白相互作用网络整合，研究胶质母细胞瘤 ceRNA 网络 (micNET) 中的 mRNA。在多个数据集中鉴定并验证了间充质 GBM 的预后 micNET 标记。确定了 micNET 和 miR181 家族成员之间的 ceRNA 相互作用。 LY2109761 是一种 TGFBR2 抑制剂，对原代培养细胞和患者来源的异种移植颅内模型均表现出肿瘤抑制作用。 结果：我们在 mRNA-miRNA 水平上表征了间充质胶质母细胞瘤，并报告了可以将间充质亚型与其他亚型区分开的 ceRNA 网络。六个基因（TGFBR2、RUNX1、PPARG、ACSL1、GIT2 和 RAP1B）以 ceRNA 相关方式和蛋白质功能相互作用，被鉴定为间充质亚型的标记。 TGFBR2 的编码序列 (CDS) 和 3'-非翻译区 (UTR) 上调这些基因的表达，而 siRNA 或 miR-181a/d 抑制 TGFBR2 则抑制其表达水平。此外，间充质亚型相关基因和侵袭表型可以通过抑制六种间充质标记基因来逆转。结论：本研究表明micNETs在间充质GBM的诊断中可能具有转化意义，并可能成为新的治疗靶点。
Rationale: Competitive endogenous RNA (ceRNA) networks play important roles in posttranscriptional regulation. Their dysregulation is common in cancer. However, ceRNA signatures have been poorly examined in the invasive and aggressive phenotypes of mesenchymal glioblastoma (GBM). This study aims to characterize mesenchymal glioblastoma at the mRNA-miRNA level and identify the mRNAs in ceRNA networks (micNET) markers and their mechanisms in tumorigenesis.Methods: The mRNAs in ceRNA networks (micNETs) of glioblastoma were investigated by constructing a GBM ceRNA network followed by integration with a STRING protein interaction network. The prognostic micNET markers of mesenchymal GBM were identified and validated across multiple datasets. ceRNA interactions were identified between micNETs and miR181 family members. LY2109761, an inhibitor of TGFBR2, demonstrated tumor-suppressive effects on both primary cultured cells and a patient-derived xenograft intracranial model.Results: We characterized mesenchymal glioblastoma at the mRNA-miRNA level and reported a ceRNA network that could separate the mesenchymal subtype from other subtypes. Six genes (TGFBR2, RUNX1, PPARG, ACSL1, GIT2 and RAP1B) that interacted with each other in both a ceRNA-related manner and in terms of their protein functions were identified as markers of the mesenchymal subtype. The coding sequence (CDS) and 3'-untranslated region (UTR) of TGFBR2 upregulated the expression of these genes, whereas TGFBR2 inhibition by siRNA or miR-181a/d suppressed their expression levels. Furthermore, mesenchymal subtype-related genes and the invasion phenotype could be reversed by suppressing the six mesenchymal marker genes.Conclusions: This study suggests that the micNETs may have translational significance in the diagnosis of mesenchymal GBM and may be novel therapeutic targets.