Inhibition of the epigenetically activated miR-483-5p/IGF-2 pathway results in rapid loss of meningioma tumor cell viability.
Inhibition of the epigenetically activated miR-483-5p/IGF-2 pathway results in rapid loss of meningioma tumor cell viability.
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抑制表观遗传活化的miR-483-5p/igf-2途径会导致脑膜瘤肿瘤细胞活力的快速丧失。
DOI：
10.1007/s11060-023-04264-z
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发表时间：
2023-03
影响因子：
3.9
通讯作者：
Krichevsky, Anna M.
中科院分区：
文献类型：
--
作者：
Uhlmann, Erik J.;Mackel, Charles E.;Deforzh, Evgeny;Rabinovsky, Rosalia;Brastianos, Priscilla K.;Varma, Hemant;Vega, Rafael A.;Krichevsky, Anna M.
脑膜瘤是最常见的原发性中枢神经系统肿瘤，常引起严重的并发症，目前尚无药物治疗。本研究的目的是发现脑膜瘤中表达异常的miRNAs，并探索适合治疗干预的miRNAs相关通路。对脑膜瘤肿瘤样本进行小RNA测序，以研究microRNA表达的等级依赖性变化。通过染色质标记、qRT-PCR和western blot分析基因表达。在脑膜瘤细胞的肿瘤来源的原代培养物中评价了miRNA调节、抗IGF-2中和抗体和IGF 1 R抑制剂。脑膜瘤肿瘤样品显示miR-483- 5 p的高的、等级依赖性表达，与其宿主基因IGF-2的高mRNA和蛋白表达相关。miR-483- 5 p的抑制降低了培养的脑膜瘤细胞的生长，而miR-483模拟物增加了细胞增殖。类似地，用抗IGF-2中和抗体抑制该途径可降低脑膜瘤细胞增殖。小分子酪氨酸激酶抑制剂阻断IGF-2受体（IGF 1 R）导致培养的脑膜瘤肿瘤衍生细胞活力迅速丧失，表明自分泌IGF-2反馈对脑膜瘤肿瘤细胞存活和生长是必需的。在基于细胞的试验中观察到的GSK 1838705 A和塞瑞替尼的IGF 1抑制IC 50沿着可用的药代动力学数据，预测作为脑膜瘤的新药物治疗，可以在体内达到有效的药物浓度。脑膜瘤细胞生长严重依赖于自分泌miR-483/IGF-2刺激，IGF-2途径提供了可行的脑膜瘤治疗靶点。在线版本包含补充材料，可通过10.1007/s11060-023-04264-z获得。
Meningioma is the most common primary central nervous system tumor often causing serious complications, and presently no medical treatment is available. The goal of this study was to discover miRNAs dysregulated in meningioma, and explore miRNA-associated pathways amenable for therapeutic interventions. Small RNA sequencing was performed on meningioma tumor samples to study grade-dependent changes in microRNA expression. Gene expression was analyzed by chromatin marks, qRT-PCR and western blot. miRNA modulation, anti-IGF-2 neutralizing antibodies, and inhibitors against IGF1R were evaluated in a tumor-derived primary cultures of meningioma cells. Meningioma tumor samples showed high, grade-dependent expression of miR-483-5p, associated with high mRNA and protein expression of its host gene IGF-2. Inhibition of miR-483-5p reduced the growth of cultured meningioma cells, whereas a miR-483 mimic increased cell proliferation. Similarly, inhibition of this pathway with anti-IGF-2 neutralizing antibodies reduced meningioma cell proliferation. Small molecule tyrosine kinase inhibitor blockade of the IGF-2 receptor (IGF1R) resulted in rapid loss of viability of cultured meningioma tumor-derived cells, suggesting that autocrine IGF-2 feedback is obligatory for meningioma tumor cell survival and growth. The observed IGF1R-inhibitory IC50 for GSK1838705A and ceritinib in cell-based assays along with the available pharmacokinetics data predicted that effective drug concentration could be achieved in vivo as a new medical treatment of meningioma. Meningioma cell growth is critically dependent on autocrine miR-483/IGF-2 stimulation and the IGF-2 pathway provides a feasible meningioma treatment target. The online version contains supplementary material available at 10.1007/s11060-023-04264-z.
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影响因子：
4.1
作者：
Rogers L;Barani I;Chamberlain M;Kaley TJ;McDermott M;Raizer J;Schiff D;Weber DC;Wen PY;Vogelbaum MA
通讯作者：
Vogelbaum MA
影响因子：
2
作者：
Baxter, David S.;Orrego, Abiel;Mathiesen, Tiit
通讯作者：
Mathiesen, Tiit
影响因子：
168.9
作者：
Soria, Jean-Charles;Tan, Daniel S. W.;de Castro, Gilberto, Jr.
通讯作者：
de Castro, Gilberto, Jr.
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
--
作者：
Donkers, Hannah;Bekkers, Ruud;Galaal, Khadra
通讯作者：
Galaal, Khadra