Identification of a Novel Prognostic Signature Based on N-Linked Glycosylation and Its Correlation with Immunotherapy Response in Hepatocellular Carcinoma.
Identification of a Novel Prognostic Signature Based on N-Linked Glycosylation and Its Correlation with Immunotherapy Response in Hepatocellular Carcinoma.
复制标题
DOI：
10.2147/jhc.s417407
复制
发表时间：
2023
影响因子：
4.1
通讯作者：
中科院分区：
文献类型：
--
作者：
肝细胞癌（HCC）复杂的肿瘤微环境导致免疫检查点抑制剂（ICIs）应答低，预后差。作为ICIs的适应症之一，PD-L1富含糖基化修饰，导致ICIs的过早发生。本研究构建了基于n -链糖基化相关基因的预后模型，用于预测预后和对ICIs的反应。n -链糖基化相关基因列表来自AmiGO2数据库。入选癌症基因组图谱（TCGA）和基因表达图谱（GEO）队列的患者。采用Cox回归建立预后模型，并将患者分为低危亚组和高危亚组。通过预后分析、基因集富集分析和免疫浸润分析，研究了signature在HCC中的作用。我们招募了21例术后接受辅助ICIs的复发性HCC患者，以评估免疫治疗反应与签名的关系。体外研究DDOST、STT3A和TMEM165在HCC中的致癌作用。在TCGA队列中从HCC和正常组织中筛选59个n -链糖基化相关差异表达基因。采用DDOST、STT3A和TMEM165建立预后模型。风险评分可能是一个独立的预后因素。高危亚组患者预后较低危亚组患者差。ssGSEA显示，低风险亚组患者倾向于处于免疫激活状态，TCGC和GEO队列中B细胞和巨噬细胞浸润水平较高，调节性T细胞（Treg）浸润水平较低。免疫组织化学研究表明，DDOST、STT3A和TMEM165在肿瘤组织中高表达，高危评分患者与无进展生存期差和免疫治疗反应差相关。此外，敲除DDOST后，以及敲除STT3A和TMEM165后，HCC细胞的增殖能力降低。在本研究中，我们建立了基于n -链糖基化相关基因的风险模型，可以有效预测HCC患者的预后和肿瘤微环境免疫状态，风险评分可以作为免疫治疗的新指标。
The complex tumor microenvironment of hepatocellular carcinoma (HCC) has led to a low response to immune checkpoints inhibitors (ICIs) and a poor prognosis. PD-L1, as one of the indications for ICIs, is rich in glycosylation modifications, which result in untimely ICIs. Our study constructed a prognostic model based on N-linked glycosylation related genes for predicting the prognosis and the response to ICIs. The list of N-linked glycosylation related genes is from the AmiGO2 database. The patients in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts were enrolled. The Cox regression was performed to develop a prognostic model and patients were divided into a low- and high-risk subgroups. The role of signature in HCC was well investigated by prognostic analysis, gene set enrichment analysis, and immune infiltration analysis. 21 recurrent HCC patients who received postoperative adjuvant ICIs were recruited to evaluate the relationship between immunotherapy response and the signature. In vitro studies were conducted to investigate the oncogenic effects of DDOST, STT3A and TMEM165 in HCC. 59 N-linked glycosylation related differentially expressed genes were screened from HCC and normal tissues in the TCGA cohort. The prognostic model was developed with DDOST, STT3A and TMEM165. The risk score could be an independent prognostic factor. Patients in the high-risk subgroup showed a worse prognosis than patients in the low-risk one. ssGSEA showed that patients in the low-risk subgroup tended to be in the immune-activated state, with higher levels of B cell and macrophage cell infiltrations and lower levels of regulatory T cell (Treg) infiltrations in both TCGC and GEO cohorts. Immunohistochemistry studies showed that DDOST, STT3A and TMEM165 are highly expressed in tumor tissues and patients with a high-risk score correlated with poor progression free survival and worse immunotherapeutic response. Furthermore, the proliferation of HCC cells was reduced after the knockdown of DDOST, as well as upon the knockdown of STT3A and TMEM165. In this study, we establish that the risk model based on N-linked glycosylation related genes could efficiently predict the prognosis and tumor microenvironment immune state of HCC patients, and the risk score could serve as a novel indicator of immunotherapy.
影响因子：
4.6
作者：
Zhuang A;Yap FY;Bruce C;Leung C;Plan MR;Sullivan MA;Herath C;McCarthy D;Sourris KC;Kantharidis P;Coughlan MT;Febbraio MA;Hodson MP;Watt MJ;Angus P;Schulz BL;Forbes JM
通讯作者：
Forbes JM