Lin Zhu, Huang Zhenkun, Shi Yunxing, Yuan Yichuan, Niu Yi, Li Binkui, Yuan Yunfei, Qiu Jiliang
State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.
Cancer Cell Int. 2023 Apr 4;23(1):59. doi: 10.1186/s12935-023-02907-9.
Non-homologous DNA end joining (NHEJ) is the predominant DNA double-strand break (DSB) repair pathway in human. However, the relationship between NHEJ pathway and hepatocellular carcinoma (HCC) is unclear. We aimed to explore the potential prognostic role of NHEJ genes and to develop an NHEJ-based prognosis signature for HCC.
Two cohorts from public database were incorporated into this study. The Kaplan-Meier curve, the Least absolute shrinkage and selection operator (LASSO) regression analysis, and Cox analyses were implemented to determine the prognostic genes. A NHEJ-related risk model was created and verified by independent cohorts. We derived enriched pathways between the high- and low-risk groups using Gene Set Enrichment Analysis (GSEA). CIBERSORT and microenvironment cell populations-counter algorithm were used to perform immune infiltration analysis. XRCC6 is a core NHEJ gene and immunohistochemistry (IHC) was further performed to elucidate the prognostic impact. In vitro proliferation assays were conducted to investigate the specific effect of XRCC6.
A novel NHEJ-related risk model was developed based on 6 NHEJ genes and patients were divided into distinct risk groups according to the risk score. The high-risk group had a poorer survival than those in the low-risk group (P < 0.001). Meanwhile, an obvious discrepancy in the landscape of the immune microenvironment also indicated that distinct immune status might be a potential determinant affecting prognosis as well as immunotherapy reactiveness. High XRCC6 expression level associates with poor outcome in HCC. Moreover, XRCC6 could promote HCC cell proliferation in vitro.
In brief, this work reveals a novel NHEJ-related risk signature for prognostic evaluation of HCC patients, which may be a potential biomarker of HCC immunotherapy.
非同源DNA末端连接（NHEJ）是人类主要的DNA双链断裂（DSB）修复途径。然而，NHEJ途径与肝细胞癌（HCC）之间的关系尚不清楚。我们旨在探讨NHEJ基因的潜在预后作用，并开发一种基于NHEJ的HCC预后特征。
将来自公共数据库的两个队列纳入本研究。采用Kaplan-Meier曲线、最小绝对收缩和选择算子（LASSO）回归分析以及Cox分析来确定预后基因。创建了一个NHEJ相关风险模型，并通过独立队列进行验证。我们使用基因集富集分析（GSEA）得出高风险组和低风险组之间的富集途径。使用CIBERSORT和微环境细胞群体计数算法进行免疫浸润分析。XRCC6是一个核心NHEJ基因，进一步进行免疫组织化学（IHC）以阐明其预后影响。进行体外增殖试验以研究XRCC6的具体作用。
基于6个NHEJ基因开发了一种新的NHEJ相关风险模型，并根据风险评分将患者分为不同的风险组。高风险组的生存率低于低风险组（P < 0.001）。同时，免疫微环境格局的明显差异也表明，不同的免疫状态可能是影响预后以及免疫治疗反应性的潜在决定因素。XRCC6高表达水平与HCC的不良预后相关。此外，XRCC6在体外可促进HCC细胞增殖。
简而言之，这项工作揭示了一种用于HCC患者预后评估的新的NHEJ相关风险特征，这可能是HCC免疫治疗的潜在生物标志物。
