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通过调节 RRM2 和 JNK 信号通路鉴定 CDKL3 作为神经胶质瘤发生发展的关键调控因子。

Identification of CDKL3 as a critical regulator in development of glioma through regulating RRM2 and the JNK signaling pathway.

机构信息

Department of Neurosurgery, Third Affiliated Hospital, Naval Medical University, Shanghai, China.

Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, China.

出版信息

Cancer Sci. 2021 Aug;112(8):3150-3162. doi: 10.1111/cas.15010. Epub 2021 Jun 28.

DOI:10.1111/cas.15010
PMID:34097336
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8353949/
Abstract

Glioma is one of the most commonly diagnosed intracranial malignancies. The molecular mechanism underlying the development of glioma is still largely unknown. In this study, we present the first report concerning the function and mechanism of cyclin-dependent kinase-like 3 (CDKL3) in the development and prognosis of glioma. It is shown that CDKL3 was upregulated in glioma tissues and could independently predict poor prognosis of patients. Silencing CDKL3 in glioma cells could inhibit cell proliferation and migration and induce cell apoptosis and cell cycle arrest, whereas the overexpression of CDKL3 promoted cell proliferation. The in vivo experiments also indicated that knockdown of CDKL3 significantly suppressed tumor growth of glioma. Gene expression profiling of CDKL3 knockdown U87 cells identified RRM2 as a potential target of CDKL3, which was proved to have direct interaction with CDKL3. Given similar effects on glioma development with CDKL3, knockdown of RRM2 could rescue the effects of CDKL3 overexpression on glioma cells. Moreover, knockdown of CDKL3 or RRM2 suppressed the activity of JNK signaling, whereas CDKL3 overexpression produced the opposite effect. In conclusion, our results identified CDKL3 as a promotor for glioma, probably through the regulation of RRM2 and activation of the JNK signalling pathway, highlighting the significance of CDKL3 as a promising therapeutic target of glioma.

摘要

神经胶质瘤是最常见的颅内恶性肿瘤之一。神经胶质瘤发生的分子机制在很大程度上尚不清楚。在本研究中，我们首次报道了周期蛋白依赖性激酶样 3（CDKL3）在神经胶质瘤发生和预后中的功能和机制。结果表明，CDKL3 在神经胶质瘤组织中上调，可独立预测患者预后不良。沉默神经胶质瘤细胞中的 CDKL3 可抑制细胞增殖和迁移，并诱导细胞凋亡和细胞周期停滞，而 CDKL3 的过表达则促进细胞增殖。体内实验也表明，CDKL3 的敲低显著抑制了神经胶质瘤的肿瘤生长。CDKL3 敲低 U87 细胞的基因表达谱鉴定出 RRM2 是 CDKL3 的一个潜在靶点，证明其与 CDKL3 有直接相互作用。鉴于 CDKL3 对神经胶质瘤发生的影响相似，敲低 RRM2 可以挽救 CDKL3 过表达对神经胶质瘤细胞的影响。此外，敲低 CDKL3 或 RRM2 抑制了 JNK 信号通路的活性，而 CDKL3 的过表达则产生了相反的效果。总之，我们的研究结果表明 CDKL3 是神经胶质瘤的一个促进因子，可能是通过调节 RRM2 和激活 JNK 信号通路，突出了 CDKL3 作为神经胶质瘤有前途的治疗靶点的重要性。

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