Characterization of endoplasmic reticulum stress unveils ZNF703 as a promising target for colorectal cancer immunotherapy.
Characterization of endoplasmic reticulum stress unveils ZNF703 as a promising target for colorectal cancer immunotherapy.
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DOI：
10.1186/s12967-023-04547-z
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发表时间：
2023-10-11
影响因子：
7.4
通讯作者：
Huang, Rui
中科院分区：
文献类型：
--
作者：
Wang, Hufei;Li, Zhi;Tao, Yangbao;Ou, Suwen;Ye, Jinhua;Ran, Songlin;Luo, Kangjia;Guan, Zilong;Xiang, Jun;Yan, Guoqing;Wang, Yang;Ma, Tianyi;Yu, Shan;Song, Yanni;Huang, Rui
结直肠癌（Colorectal cancer，CRC）是全球最常见的恶性肿瘤之一，发病率和死亡率都很高。内质网是负责蛋白质合成、加工和运输的主要细胞器。内质网应激（Endoplasmic reticulum stress，ERS）是指内质网中未折叠和错误折叠蛋白质的异常积累，与肿瘤发生和肿瘤免疫有关。然而，ERS在CRC中的临床意义在很大程度上仍未被探索。在本研究中，我们进行了无监督聚类，以确定两种类型的ERS相关亚型[ERS簇，和ERS相关基因（ERSGs）簇]在多个大规模的CRC队列。通过利用机器学习技术，我们成功地开发了一个简单而强大的基因评分系统（ERSGs签名）。此外，一系列分析，包括GO，KEGG，肿瘤免疫功能障碍和排斥（TIDE），共识分子亚型（CMS），用于探讨这些组之间的潜在生物学差异和临床意义。对ERSGs评分系统基因ZNF 703进行免疫组织化学和生物信息学分析。我们观察到ERS集群和ERSGs集群之间的预后和肿瘤免疫状态的显着差异。ERSGs评分系统是总生存期的独立危险因素;在多中心CRC队列中显示出不同的肿瘤免疫状态。此外，TNM分期、CMS组分析显示，晚期和CMS 4级患者的ERSGs评分较高。此外，ERSG评分与阳性ICB应答预测因子（如CD 8A、CD 274（PD-L1）和TIS）呈负相关，与阴性ICB应答预测因子（如TIDE、T细胞排除、COX-IS）呈直接相关。免疫组织化学染色和生物信息学分析显示ZNF 70与CD 3+和CD 8 + T细胞浸润相关。本研究基于大规模、多中心的转录组学数据，全面揭示ERS在结直肠癌中的重要作用，并构建了一个新的ERSGs评分系统，用于预测患者的预后和ICB治疗的疗效。此外，我们将ZNF 703确定为CRC ICB治疗的潜在有希望的靶点。在线版本包含补充材料，可通过10.1186/s12967-023-04547-z获得。
Colorectal cancer (CRC) is one of the most common malignant tumors globally, with high morbidity and mortality. Endoplasmic reticulum is a major organelle responsible for protein synthesis, processing, and transport. Endoplasmic reticulum stress (ERS) refers to the abnormal accumulation of unfolded and misfolded proteins in the endoplasmic reticulum, which are involved in tumorigenesis and cancer immunity. Nevertheless, the clinical significance of ERS remains largely unexplored in CRC. In present study, we performed an unsupervised clustering to identify two types of ERS-related subtypes [ERS clusters, and ERS-related genes (ERSGs) clusters] in multiple large-scale CRC cohorts. Through the utilization of machine learning techniques, we have successfully developed an uncomplicated yet robust gene scoring system (ERSGs signature). Furthermore, a series of analyses, including GO, KEGG, Tumor Immune Dysfunction and Exclusion (TIDE), the Consensus Molecular Subtypes (CMS), were used to explore the underlying biological differences and clinical significance between these groups. And immunohistochemical and bioinformatics analyses were performed to explore ZNF703, a gene of ERSGs scoring system. We observed significant differences in prognosis and tumor immune status between the ERS clusters as well as ERSGs clusters. And the ERSGs scoring system was an independent risk factor for overall survival; and exhibited distinct tumor immune status in multicenter CRC cohorts. Besides, analyses of TNM stages, CMS groups demonstrated that patients in advanced stage and CMS4 had higher ERSGs scores. In addition, the ERSGs scores inversely correlated with positive ICB response predictors (such as, CD8A, CD274 (PD-L1), and TIS), and directly correlated with negative ICB response predictors (such as, TIDE, T cell Exclusion, COX-IS). Notably, immunohistochemical staining and bioinformatics analyses revealed that ZNF70 correlated with CD3 + and CD8 + T cells infiltration. Based on large-scale and multicenter transcriptomic data, our study comprehensively revealed the essential role of ERS in CRC; and constructed a novel ERSGs scoring system to predict the prognosis of patients and the efficacy of ICB treatment. Furthermore, we identified ZNF703 as a potentially promising target for ICB therapy in CRC. The online version contains supplementary material available at 10.1186/s12967-023-04547-z.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
64.5
作者：
Cubillos-Ruiz JR;Silberman PC;Rutkowski MR;Chopra S;Perales-Puchalt A;Song M;Zhang S;Bettigole SE;Gupta D;Holcomb K;Ellenson LH;Caputo T;Lee AH;Conejo-Garcia JR;Glimcher LH
通讯作者：
Glimcher LH
影响因子：
5.8
作者：
Chakraborty, Sutirtha;Datta, Somnath;Datta, Susmita
通讯作者：
Datta, Susmita
DOI：
10.1073/pnas.0914072107
发表时间：
2010-08-31
影响因子：
11.1
作者：
Auf, Gregor;Jabouille, Arnaud;Moenner, Michel
通讯作者：
Moenner, Michel
影响因子：
6.5
作者：
Fagone, Paolo;Jackowski, Suzanne
通讯作者：
Jackowski, Suzanne