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.

Keywords: ceRNA network, micNETs, TGFBR2, mesenchymal subtype

基本原理：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。但是，在间充质胶质母细胞瘤（GBM）的侵袭性和侵袭性表型中，ceRNA的签名研究得很差。这项研究旨在表征间质性胶质母细胞瘤的mRNA-miRNA水平，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（micNETs）中的mRNA。间质性GBM的预后性micNET标记物已在多个数据集中进行了鉴定和验证。在NET和miR181家族成员之间鉴定了ceRNA相互作用。LY2109761，TGFBR2的抑制剂，对原代培养细胞和患者来源的异种移植颅内模型均显示出肿瘤抑制作用。

结果：我们在mRNA-miRNA水平上表征了间充质胶质母细胞瘤，并报道了可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相关的方式和蛋白质功能相互相互作用，被鉴定为间充质亚型的标志物。TGFBR2的编码序列（CDS）和3'-非翻译区（UTR）上调了这些基因的表达，而siRNA或miR-181a / d对TGFBR2的抑制则抑制了它们的表达水平。此外，通过抑制六个间充质标记基因可以逆转与间充质亚型相关的基因和侵袭表型。

结论：这项研究表明，micNETs在间充质GBM的诊断中可能具有翻译意义，并且可能是新的治疗靶标。

关键词：ceRNA网络，micNETs，TGFBR2，间充质亚型