Background: Hepatocellular carcinoma (HCC) is characterized by high vascularity and notable abnormality of blood vessels, where angiogenesis is a key process in tumorigenesis and metastasis. The main functions of Nei Like DNA Glycosylase 3 (NEIL3) include DNA alcoholization repair, immune response regulation, nervous system development and function, and DNA damage signal transduction. However, the underlying mechanism of high expression NEIL3 in the development and progression of HCC and whether the absence or silencing of NEIL3 inhibits the development of cancer remain unclear. Therefore, a deeper understanding of the mechanisms by which increased NEIL3 expression promotes cancer development is needed. Methods: Expression of NEIL3 and its upstream transcription factor MAZ in HCC tumor tissues was analyzed in bioinformatics efforts, while validation was done by qRT-PCR and western blot in HCC cell lines. The migration and tube formation capacity of HUVEC cells were analyzed by Transwell and tube formation assays. Glycolytic capacity was analyzed by extracellular acidification rate, glucose uptake, and lactate production levels. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter gene assays were utilized to investigate specific interactions between MAZ and NEIL3. Results: NEIL3 and MAZ were substantially upregulated in HCC tissues and cells. NEIL3 was involved in modulating the glycolysis pathway, suppression of which reversed the stimulative impact of NEIL3 overexpression on migration and angiogenesis in HUVEC cells. MAZ bound to the promoter of NEIL3 to facilitate NEIL3 transcription. Silencing MAZ reduced NEIL3 expression and suppressed the glycolysis pathway, HUVEC cell migration, and angiogenesis. Conclusion: MAZ potentiated the upregulated NEIL3-mediated glycolysis pathway and HCC angiogenesis. This study provided a rationale for the MAZ/NEIL3/glycolysis pathway as a possible option for anti-angiogenesis therapy in HCC.

中文翻译：

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转录因子 MAZ 增强 NEIL3 介导的有氧糖酵解上调，从而促进肝细胞癌中的血管生成

背景：肝细胞癌（HCC）具有高血管分布和显着的血管异常的特点，其中血管生成是肿瘤发生和转移的关键过程。Nei Like DNA糖基化酶3（NEIL3）的主要功能包括DNA醇化修复、免疫反应调节、神经系统发育和功能以及DNA损伤信号转导。然而，高表达NEIL3在HCC发生和进展中的潜在机制以及NEIL3的缺失或沉默是否抑制癌症的发展仍不清楚。因此，需要更深入地了解 NEIL3 表达增加促进癌症发展的机制。方法：通过生物信息学分析肝癌肿瘤组织中NEIL3及其上游转录因子MAZ的表达，并通过qRT-PCR和蛋白质印迹在肝癌细胞系中进行验证。通过Transwell和成管实验分析HUVEC细胞的迁移和成管能力。通过细胞外酸化率、葡萄糖摄取和乳酸产生水平来分析糖酵解能力。利用染色质免疫沉淀 (ChIP) 和双荧光素酶报告基因测定来研究 MAZ 和 NEIL3 之间的特异性相互作用。结果：NEIL3 和 MAZ 在 HCC 组织和细胞中显着上调。NEIL3 参与调节糖酵解途径，抑制该途径可逆转 NEIL3 过表达对 HUVEC 细胞迁移和血管生成的刺激影响。MAZ 与 NEIL3 的启动子结合以促进 NEIL3 转录。沉默 MAZ 可减少 NEIL3 表达并抑制糖酵解途径、HUVEC 细胞迁移和血管生成。结论：MAZ 增强了 NEIL3 介导的糖酵解途径和 HCC 血管生成的上调。这项研究为 MAZ/NEIL3/糖酵解途径作为 HCC 抗血管生成治疗的可能选择提供了理论依据。