Long non-coding RNAs play critical roles in tumour progression. Through analysis of publicly available genomic datasets, we found that MIR22HG, the host gene of microRNAs miR-22-3p and miR-22-5p, is ranked among the most dysregulated long non-coding RNAs in glioblastoma. The main purpose of this work was to determine the impact of MIR22HG on glioblastoma growth and invasion and to elucidate its mechanistic function. The MIR22HG/miR-22 axis was highly expressed in glioblastoma as well as in glioma stem-like cells compared to normal neural stem cells. In glioblastoma, increased expression of MIR22HG is associated with poor prognosis. Through a number of functional studies, we show that MIR22HG silencing inhibits the Wnt/β-catenin signalling pathway through loss of miR-22-3p and -5p. This leads to attenuated cell proliferation, invasion and in vivo tumour growth. We further show that two genes, SFRP2 and PCDH15, are direct targets of miR-22-3p and -5p and inhibit Wnt signalling in glioblastoma. Finally, based on the 3D structure of the pre-miR-22, we identified a specific small-molecule inhibitor, AC1L6JTK, that inhibits the enzyme Dicer to block processing of pre-miR-22 into mature miR-22. AC1L6JTK treatment caused an inhibition of tumour growth in vivo. Our findings show that MIR22HG is a critical inducer of the Wnt/β-catenin signalling pathway, and that its targeting may represent a novel therapeutic strategy in glioblastoma patients.

中文翻译：

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通过抑制Wnt /β-catenin信号传导，干扰长时间的非编码RNA MIR22HG加工可抑制胶质母细胞瘤的进展。

长的非编码RNA在肿瘤进展中起关键作用。通过对公开可用的基因组数据集的分析，我们发现MIR22HG是miRNA-22-3p和miR-22-5p的宿主基因，在胶质母细胞瘤中位居最失调的长非编码RNA之一。这项工作的主要目的是确定MIR22HG对胶质母细胞瘤生长和侵袭的影响，并阐明其机制功能。与正常的神经干细胞相比，MIR22HG / miR-22轴在胶质母细胞瘤和神经胶质瘤干样细胞中高表达。在胶质母细胞瘤中，MIR22HG的表达增加与预后不良有关。通过大量的功能研究，我们表明MIR22HG沉默通过丢失miR-22-3p和-5p抑制Wnt /β-catenin信号传导途径。这会导致细胞增殖减弱，侵袭和体内肿瘤生长。我们进一步表明，两个基因，SFRP2和PCDH15，是miR-22-3p和-5p的直接靶标，并抑制胶质母细胞瘤中的Wnt信号传导。最后，基于premiR-22的3D结构，我们确定了一种特定的小分子抑制剂AC1L6JTK，该抑制剂抑制Dicer酶来阻止premiR-22加工成成熟的miR-22。AC1L6JTK治疗导致体内肿瘤生长受到抑制。我们的发现表明，MIR22HG是Wnt /β-catenin信号传导途径的关键诱导剂，其靶向作用可能代表胶质母细胞瘤患者的新型治疗策略。我们确定了一种特定的小分子抑制剂AC1L6JTK，该抑制剂可抑制Dicer酶以阻止pre-miR-22加工成成熟的miR-22。AC1L6JTK治疗导致体内肿瘤生长受到抑制。我们的发现表明，MIR22HG是Wnt /β-catenin信号传导途径的关键诱导剂，其靶向作用可能代表胶质母细胞瘤患者的新型治疗策略。我们确定了一种特定的小分子抑制剂AC1L6JTK，该抑制剂可抑制Dicer酶以阻止pre-miR-22加工成成熟的miR-22。AC1L6JTK治疗导致体内肿瘤生长受到抑制。我们的发现表明，MIR22HG是Wnt /β-catenin信号传导途径的关键诱导剂，其靶向作用可能代表胶质母细胞瘤患者的新型治疗策略。