文章：

RACK1通过阻止CSNK2B泛素化降解激活NF-κB通路促进脑膜瘤进展

RACK1 Promotes Meningioma Progression by Activation of NF-κB Pathway via Preventing CSNK2B from Ubiquitination Degradation

原文发布日期：13 February 2024

DOI: 10.3390/cancers16040767

类型: Article

开放获取: 是

英文摘要：

Higher-grade meningiomas (WHO grade II and III) are characterized by aggressive invasiveness and high postoperative recurrence rates. The prognosis remains inadequate even with adjuvant radiotherapy and currently there is no definitive pharmacological treatment strategy and target for malignant meningiomas. This study aims to unveil the mechanisms driving the malignant progression of meningiomas and to identify potential inhibitory targets, with significant clinical implications. Implementing techniques such as protein immunoprecipitation, mass spectrometry, RNA interference, and transcriptome sequencing, we investigated the malignancy mechanisms in meningioma cell lines IOMM-LEE and CH157-MN. Additionally, in vivo experiments were carried out on nude mice. We discovered a positive correlation between meningioma malignancy and the levels of the receptor for activated C kinase 1 (RACK1), which interacts with CSNK2B, the β subunit of casein kinase 2 (CK2), inhibiting its ubiquitination and subsequent degradation. This inhibition allows CK2 to activate the NF-κb pathway, which increases the transcription of CDK4 and cyclin D3, resulting in the transition of the cell cycle into the G2/M phase. The RACK1 inhibitor, harringtonolide (HA), significantly suppressed the malignant tendencies of meningioma cells. Our study suggests that RACK1 may play a role in the malignant progression of meningiomas, and therefore, targeting RACK1 could emerge as an effective strategy for reducing the malignancy of these tumors.

摘要翻译： 

高级别脑膜瘤（WHO II级和III级）具有侵袭性强、术后复发率高的特点。即使辅以放射治疗，其预后仍不理想，目前尚无针对恶性脑膜瘤的明确药物治疗策略及靶点。本研究旨在揭示驱动脑膜瘤恶性进展的机制并寻找潜在抑制靶点，具有重要的临床意义。通过采用蛋白质免疫共沉淀、质谱分析、RNA干扰及转录组测序等技术，我们在脑膜瘤细胞系IOMM-LEE和CH157-MN中探究了恶性化机制，并开展了裸鼠体内实验。研究发现脑膜瘤恶性程度与活化C激酶1受体（RACK1）水平呈正相关，RACK1与酪蛋白激酶2（CK2）的β亚基CSNK2B相互作用，抑制其泛素化及后续降解，从而促使CK2激活NF-κB通路，进而增强CDK4和细胞周期蛋白D3的转录，最终推动细胞周期进入G2/M期。RACK1抑制剂三尖杉宁碱（HA）能显著抑制脑膜瘤细胞的恶性表型。本研究提示RACK1可能在脑膜瘤恶性进展中发挥重要作用，靶向RACK1有望成为降低此类肿瘤恶性程度的有效策略。

原文链接：

RACK1 Promotes Meningioma Progression by Activation of NF-κB Pathway via Preventing CSNK2B from Ubiquitination Degradation