背景:铁凋亡与肿瘤的免疫抑制有关,并在癌症进展中起关键作用。范可尼贫血互补组D2(FANCD2)是调节铁凋亡的重要基因。然而,FANCD2在乙型肝炎相关肝细胞癌(HCC)中的作用机制尚不清楚。在这项研究中,我们调查了FANCD2在乙型肝炎相关HCC中的预后意义和作用机制。
方法:使用癌症基因组图谱(TCGA)探索乙型肝炎相关HCC中FANCD2的表达,并使用基因表达综合(GEO)数据库进行验证。单变量和多变量Cox回归分析和Kaplan-Meier生存曲线用于分析FANCD2表达与乙型肝炎相关HCC患者总体生存之间的关系。使用STRING网站构建FANCD2的蛋白质-蛋白质相互作用网络。此外,FANCD2表达与干燥指数的相关性,肿瘤突变负担,微卫星不稳定性(MSI),免疫途径,参与铁代谢的基因,和索拉非尼化疗反应进行分析。
结果:我们的结果表明,FANCD2在乙型肝炎相关的HCC中明显过表达,并表现出很强的诊断预测能力(曲线下面积,0.903)和疾病的预后。FANCD2高表达与不良预后相关,高级别肿瘤,PDL-1的高表达,高MSI评分,索拉非尼在乙型肝炎相关HCC中的IC50较低。BRCA1、BRCA2、FAN1和FANCC是与FANCD2相互作用的重要蛋白。FANCD2的表达水平与Treg细胞的浸润水平显著相关,B细胞,CD8+T细胞,CD4+T细胞,中性粒细胞,巨噬细胞,髓样树突状细胞,和NK细胞在乙型肝炎相关肝癌。FANCD2与肿瘤增殖信号通路呈正相关,DNA修复,和细胞对缺氧的反应。
结论:我们的研究表明,FANCD2是一个潜在的新的生物标志物和免疫治疗靶点对乙型肝炎相关的肝癌,这可能与索拉非尼的化疗反应有关。
BACKGROUND: Ferroptosis is related to the immunosuppression of tumors and plays a critical role in cancer progression. Fanconi anemia complementation group D2 (FANCD2) is a vital gene that regulates ferroptosis. However, the mechanism of action of FANCD2 in Hepatitis B-related hepatocellular carcinoma (HCC) remains unknown. In this study, we investigated the prognostic significance and mechanism of action of FANCD2 in Hepatitis B-related HCC.
METHODS: The expression of FANCD2 in Hepatitis B-related HCC was explored using The Cancer Genome Atlas (TCGA) and validated using the Gene Expression Omnibus (GEO) database. Univariate and multivariate Cox regression analyses and Kaplan-Meier survival curves were used to analyze the relationship between FANCD2 expression and the overall survival of patients with Hepatitis B-related HCC. Protein-protein interaction networks for FANCD2 were built using the STRING website. In addition, correlations between FANCD2 expression and the dryness index, tumor mutational burden, microsatellite instability (MSI), immune pathways, genes involved in iron metabolism, and sorafenib chemotherapeutic response were analyzed.
RESULTS: Our results indicated that FANCD2 was significantly overexpressed in Hepatitis B-related HCC and demonstrated a strong predictive ability for diagnosis (Area Under Curve, 0.903) and prognosis of the disease. High FANCD2 expression was associated with poor prognosis, high-grade tumors, high expression of PDL-1, high MSI scores, and low sorafenib IC50 in Hepatitis B-related HCC. BRCA1, BRCA2, FAN1, and FANCC were vital proteins interacting with FANCD2. The expression level of FANCD2 significantly correlated with the infiltration levels of Treg cells, B cells, CD8 + T cells, CD4 + T cells, neutrophils, macrophages, myeloid dendritic cells, and NK cells in Hepatitis B-related HCC. FANCD2 was positively correlated with the tumor proliferation signature pathway, DNA repair, and cellular response to hypoxia.
CONCLUSIONS: Our study indicated that FANCD2 was a potential novel biomarker and immunotherapeutic target against Hepatitis B-related HCC, which might be related to the chemotherapeutic response to sorafenib.