Li Na, Zheng Xue, Chen Mianrong, Huang Li, Chen Li, Huo Rui, Li Xiaotong, Huang Yucan, Sun Mingwen, Mai Suiqing, Wu Zhuoyi, Zhang Hui, Liu Jinbao, Yang Chun-Tao
Affiliated Cancer Hospital & Institute of Guangzhou Medical University Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation School of Basic Medical Sciences Guangzhou Medical University Guangzhou China.
Department of Pathology Yue Bei People's Hospital Shaoguan China.
Clin Transl Immunology. 2022 Apr 20;11(4):e1386. doi: 10.1002/cti2.1386. eCollection 2022.
Diabetic hepatocellular carcinoma (HCC) patients have high mortality and metastasis rates. Diabetic conditions promote neutrophil extracellular traps (NETs) generation, which mediates HCC metastasis and invasion. However, whether and how diabetes-induced NETs trigger HCC invasion is largely unknown. Here, we aimed to observe the effects of diabetes-induced NETs on HCC invasion and investigate mechanisms relevant to a DNA sensor cyclic GMP-AMP synthase (cGAS).
Serum from diabetic patients and healthy individuals was collected. Human neutrophil-derived NETs were isolated for stimulating HCC cell invasion. Data from the SEER and TCGA databases were used for bioinformatics analysis. In HCC cells and allograft models, NETs-triggered invasion was observed.
Diabetic HCC patients had poorer survival than non-diabetic ones. Either diabetic serum or extracted NETs caused HCC invasion. Induction of diabetes or NETosis elicited HCC allograft invasion in nude mice. HCC cell invasion was attenuated by the treatment with DNase1. In TCGA_LIHC, an extracellular DNase DNASE1L3 was downregulated in tumor tissues, while function terms (the endocytic vesicle membrane, the NF-κB pathway and extracellular matrix disassembly) were enriched. DNASE1L3 knockdown in LO2 hepatocytes or H22 cell-derived allografts facilitated HCC invasion in NETotic or diabetic nude mice. Moreover, exposure of HCC cells to NETs upregulated cGAS and the non-canonical NF-κB pathway and induced expression of metastasis genes ( and ). Both cGAS inhibitor and NF-κB RELB knockdown diminished HCC invasion caused by NETs DNA. Also, cGAS inhibitor was able to retard translocation of NF-κB RELB.
Defective DNASE1L3 aggravates NETs DNA-triggered HCC invasion on diabetic conditions via cGAS and the non-canonical NF-κB pathway.
糖尿病性肝细胞癌（HCC）患者具有较高的死亡率和转移率。糖尿病状态促进中性粒细胞胞外诱捕网（NETs）的生成，其介导HCC的转移和侵袭。然而，糖尿病诱导的NETs是否以及如何触发HCC侵袭在很大程度上尚不清楚。在此，我们旨在观察糖尿病诱导的NETs对HCC侵袭的影响，并研究与DNA传感器环磷酸鸟苷-腺苷酸合成酶（cGAS）相关的机制。
收集糖尿病患者和健康个体的血清。分离人中性粒细胞衍生的NETs以刺激HCC细胞侵袭。利用监测、流行病学和最终结果（SEER）及癌症基因组图谱（TCGA）数据库的数据进行生物信息学分析。在HCC细胞和同种异体移植模型中，观察NETs触发的侵袭情况。
糖尿病性HCC患者的生存率低于非糖尿病患者。糖尿病血清或提取的NETs均可导致HCC侵袭。诱导糖尿病或NETosis可引发裸鼠HCC同种异体移植侵袭。用脱氧核糖核酸酶1（DNase1）处理可减弱HCC细胞侵袭。在TCGA_LIHC中，肿瘤组织中细胞外脱氧核糖核酸酶DNASE1L3表达下调，而功能术语（内吞囊泡膜、核因子κB（NF-κB）途径和细胞外基质分解）富集。在LO2肝细胞或H22细胞衍生的同种异体移植中敲低DNASE1L3可促进NETotic或糖尿病裸鼠的HCC侵袭。此外，将HCC细胞暴露于NETs可上调cGAS和非经典NF-κB途径，并诱导转移基因（此处原文缺失具体基因名称）的表达。cGAS抑制剂和NF-κB RELB敲低均可减少NETs DNA引起的HCC侵袭。此外，cGAS抑制剂能够抑制NF-κB RELB的易位。
在糖尿病状态下，有缺陷的DNASE1L3通过cGAS和非经典NF-κB途径加重NETs DNA触发的HCC侵袭。
