失调的miRNAs可作为星形细胞瘤的潜在治疗靶点：生物信息学分析

Dysregulated miRNAs as Potential Therapeutic Targets of Astrocytoma: Bioinformatics Analysis

摘要: 目的：在神经系统常见肿瘤中，胶质瘤属于较难治疗的原发性肿瘤之一，一般具有预后较差、较高死亡率、常易复发等特点。其中，最常见的胶质瘤类型为星形细胞瘤，也是本次研究的目的。以当前的医疗水平，对胶质瘤尽早诊断和尽快进入规范化诊疗阶段是非常重要的，而从当前的治疗现状来看仍不尽人意。我们发现一种生物标志物——microRNAs (miRNAs)，在上述疾病诊断及预后过程中存在巨大潜力，近期的多项研究表明它在星形细胞瘤的发生、发展、转归中都有研究价值。故本研究的主旨是探讨miRNA失调在星形细胞瘤发生发展中的重要性，并利用生物信息学分析以确定潜在的治疗靶点。方法：我们从GEO基因表达综合数据库(下称GEO)下载GSE138764和GSE132052两个经筛选后符合要求的微阵列数据集，并使用Rv3.6.2软件和KEGG通路分析对其进行分析。结果：综合生物分析结果，与星形细胞瘤发生、发展与转归呈重要相关的miRNAs或与以下靶点有关：细胞粘附因子、RNA聚合酶II、钙粘蛋白、泛素蛋白、转录辅助活化子、组蛋白、激素-受体结合体、肿瘤蛋白多糖、细胞衰老、以及多个信号通路(MAPK, PI3K-Akt, Hippo, mTOR)等。随即，我们从中选择10个在表达中差异最明显的miRNAs进行进一步研究：miR-138-2-3p、miR-377-5p、miR-517c-3p、miR-770-5p、miR-431-3p、miR-29b-2-5p、miR-433、miR-212-5p、miR-517a-3p、miR-490-3p，并发现，这些miRNA或与肿瘤细胞的增殖、迁移和侵袭等生理病理过程有关。结论：这些发现向我们揭示：星形细胞瘤的发生、发展及转归可能与miRNAs失调有关，NUPL2，miR-517c-3p和miR-431-3p等基因可能在进一步研究后证明对于星形细胞瘤具有重要的诊断价值，可以作为潜在的生物治疗靶点进行应用。

Abstract: Purpose: Glioma is one of the primary tumors that are difficult to treat in common nervous system tumors, which is generally characterized by poor prognosis, high mortality, and easy recurrence. Among them, the most common type of glioma is astrocytoma, which is also the purpose of this study. At the current level of medical treatment, early diagnosis and rapid entry into standardized diagnosis and treatment of gliomas are very important, but the current treatment status is still not satisfactory. We found that a biomarker, microRNAs (miRNAs), has great potential in the diagnosis and prognosis of the above-mentioned diseases. Many recent studies have shown that it has research value in the occurrence, development, and outcome of astrocytoma. Therefore, the main purpose of this study is to explore the importance of miRNA disorder in the occurrence and development of astrocytoma, and to use bioinformatics analysis to determine potential therapeutic targets. Methods: Two microarray datasets for GSE138764 and GSE132052 were downloaded from the Gene Expression Omnibus (GEO) database and analyzed with software Rv3.6.2, and KEGG Pathway Analysis. Results: The miRNAs implicated in astrocytoma were associated with the following targets: cell adhesion molecule, RNA polymerase II, ubiquitin protein, cadherin, transcription coactivator, histone, hormone receptor binding, proteoglycans in cancer, cellular senescence, MAPK signaling pathway, PI3K-Akt signaling pathway, Hippo signaling pathway, and mTOR signaling pathway. Next, we selected 10 miRNAs with the largest expression differences: miR-138-2-3p, miR-377-5p, miR-29b-2-5p, miR-517c-3p, miR-770-5p, miR-431-3p, miR-433, miR-212-5p, miR-517a-3p, miR-490-3p, and found that they were related to tumor cell proliferation, migration, and invasion. Conclusion: These findings suggest that dysregulated miRNAs are implicated in astrocytoma progression, and NUPL2, miR-517c-3p and miR-431-3p could be potential diagnosis biomarkers and therapeutic targets for astrocytoma.