Purpose

Meningiomas are the most common type of brain tumors and are generally benign, but malignant atypical meningiomas and anaplastic meningiomas frequently recur with poor prognosis. The metabolism of meningiomas is little known, so few effective treatment options other than surgery and radiation are available, and the targets for treatment of recurrence are not well defined. The Aim of this paper is to find the therapeutic target.

Methods

The effects of bone morphogenetic protein (BMP) signal inhibitor (K02288) and upstream regulator Gremlin2 (GREM2) on meningioma’s growth and senescence were examined. In brief, we examined as follows: 1) Proliferation assay by inhibiting BMP signaling. 2) Comprehensive analysis of forced expression GREM2.3) Correlation between GREM2 mRNA expression and proliferation marker in 87 of our clinical samples. 4) Enrichment analysis between GREM2 high/low expressed groups using RNA-seq data (42 cases) from the public database GREIN. 5) Changes in metabolites and senescence markers associated with BMP signal suppression.

Results

Inhibitors of BMP receptor (BMPR1A) and forced expression of GREM2 shifted tryptophan metabolism from kynurenine/quinolinic acid production to serotonin production in malignant meningiomas, reduced NAD + /NADH production, decreased gene cluster expression involved in oxidative phosphorylation, and caused decrease in ATP. Finally, malignant meningiomas underwent cellular senescence, decreased proliferation, and eventually formed psammoma bodies. Reanalyzed RNA-seq data of clinical samples obtained from GREIN showed that increased expression of GREM2 decreased the expression of genes involved in oxidative phosphorylation, similar to our experimental results.

Conclusions

The GREM2-BMPR1A-tryptophan metabolic pathway in meningiomas is a potential new therapeutic target.

中文翻译：

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抑制 BMP 信号通路诱导的间变性脑膜瘤衰老和钙化

目的

脑膜瘤是最常见的脑肿瘤类型，一般为良性，但恶性非典型脑膜瘤和间变性脑膜瘤经常复发，预后不良。脑膜瘤的代谢知之甚少，因此除了手术和放射之外，有效的治疗选择很少，并且复发治疗的目标尚不明确。本文的目的是寻找治疗靶点。

方法

研究了骨形态发生蛋白 (BMP) 信号抑制剂 (K02288) 和上游调节因子 Gremlin2 (GREM2) 对脑膜瘤生长和衰老的影响。简而言之，我们进行了如下检查：1)通过抑制BMP信号传导进行增殖测定。2）强制表达GREM2的综合分析。3）我们87个临床样本中GREM2 mRNA表达与增殖标志物的相关性。4）利用公共数据库GREIN的RNA-seq数据（42例）对GREM2高/低表达组之间进行富集分析。5) 与 BMP 信号抑制相关的代谢物和衰老标志物的变化。

结果

在恶性脑膜瘤中，BMP 受体 (BMPR1A) 抑制剂和 GREM2 的强制表达将色氨酸代谢从犬尿氨酸/喹啉酸的产生转变为血清素的产生，减少了 NAD + /NADH 的产生，减少了参与氧化磷酸化的基因簇表达，并导致 ATP 减少。最后，恶性脑膜瘤经历细胞衰老、增殖减少，最终形成砂粒体。重新分析从 GREIN 获得的临床样本的 RNA-seq 数据表明，GREM2 表达的增加降低了参与氧化磷酸化的基因的表达，与我们的实验结果相似。

结论

脑膜瘤中的 GREM2-BMPR1A-色氨酸代谢途径是一个潜在的新治疗靶点。