Xiao Feng, Shen Jie, Zhou Lihui, Fang Zebin, Weng Yuxiang, Zhang Chao, Zhang Luyuan, Huang Xin, Zhan Renya
Department of Neurosurgery, The 1st Affiliated Hospital, Zhejiang University School of Medicine Hangzhou, Zhejiang, China.
Zhejiang University School of Medicine Hangzhou, Zhejiang, China.
Am J Cancer Res. 2022 Sep 15;12(9):4312-4325. eCollection 2022.
The immune microenvironment of glioma attributes to the initiation and development of glioma; however, the underlying mechanisms of tumor microenvironment formation have not been fully understood. In this study, we revealed that Zinc Finger Protein 395 (ZNF395), a member of the Kruppel C2H2-type zinc-finger protein family and also known as a common transcription factor, was aberrantly overexpressed in glioma and positively associated with the poor clinicopathological features and the prognosis of patients with glioma based on the analyses of TCGA, CGGA and other datasets. Further in vitro experimental data demonstrated that the upregulation of ZNF395 promoted the proliferation of glioma cells. In addition, functional enrichment analysis showed that ZNF395 was involved in immune processes and correlated with macrophage infiltration and polarization. Moreover, C-C Motif Chemokine Ligand 20 (CCL20), one of the ZNF395 co-expressed genes, was validated as the downstream factor under the transcriptional regulation of ZNF395. Importantly, cell co-culture experiments confirmed that ZNF395 upregulated both the intracellular and secreted CCL20 level of glioma cells and induced M2 macrophage polarization which is known to promote the malignant progression of glioma. Taken together, our findings suggested that ZNF395 might play an essential role in glioma development, and inhibition of ZNF395 might be a plausible strategy for glioma therapy.
胶质瘤的免疫微环境与胶质瘤的发生发展有关；然而，肿瘤微环境形成的潜在机制尚未完全阐明。在本研究中，我们发现锌指蛋白395（ZNF395），一种属于Kruppel C2H2型锌指蛋白家族的成员，也是一种常见的转录因子，在胶质瘤中异常高表达，并且基于TCGA、CGGA和其他数据集的分析，与胶质瘤患者的不良临床病理特征和预后呈正相关。进一步的体外实验数据表明，ZNF395的上调促进了胶质瘤细胞的增殖。此外，功能富集分析表明，ZNF395参与免疫过程，并与巨噬细胞浸润和极化相关。此外，ZNF395共表达基因之一的C-C基序趋化因子配体20（CCL20）被证实为ZNF395转录调控下的下游因子。重要的是，细胞共培养实验证实，ZNF395上调了胶质瘤细胞内及分泌的CCL20水平，并诱导了已知促进胶质瘤恶性进展的M2巨噬细胞极化。综上所述,我们的研究结果表明,ZNF395可能在胶质瘤发展中起重要作用,抑制ZNF395可能是一种可行的胶质瘤治疗策略。
