Department of Colorectal Cancer Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150080, China.
Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
J Transl Med. 2023 Oct 11;21(1):713. doi: 10.1186/s12967-023-04547-z.
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.
结直肠癌（CRC）是全球最常见的恶性肿瘤之一，具有较高的发病率和死亡率。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（ERS）是指内质网中未折叠和错误折叠蛋白质的异常积累，它与肿瘤发生和癌症免疫有关。然而，ERS 在 CRC 中的临床意义在很大程度上仍未得到探索。
在本研究中，我们进行了无监督聚类，以在多个大规模 CRC 队列中识别两种类型的 ERS 相关亚型[ERS 簇和 ERS 相关基因（ERSGs）簇]。通过使用机器学习技术，我们成功开发了一种简单而稳健的基因评分系统（ERSGs 签名）。此外，进行了一系列分析，包括 GO、KEGG、肿瘤免疫功能障碍和排除（TIDE）、共识分子亚型（CMS），以探索这些组之间的潜在生物学差异和临床意义。并进行了免疫组织化学和生物信息学分析，以探索 ERSGs 评分系统中的 ZNF703 基因。
我们观察到 ERS 簇和 ERSGs 簇之间的预后和肿瘤免疫状态存在显著差异。ERSGs 评分系统是总生存期的独立危险因素；并且在多中心 CRC 队列中表现出不同的肿瘤免疫状态。此外，在 TNM 分期、CMS 组的分析中，晚期和 CMS4 患者的 ERSGs 评分更高。此外，ERSGs 评分与阳性 ICB 反应预测因子（如 CD8A、CD274（PD-L1）和 TIS）呈负相关，与阴性 ICB 反应预测因子（如 TIDE、T 细胞排除、COX-IS）呈正相关。值得注意的是，免疫组织化学染色和生物信息学分析显示 ZNF70 与 CD3+和 CD8+T 细胞浸润相关。
基于大规模和多中心转录组数据，本研究全面揭示了 ERS 在 CRC 中的重要作用；并构建了一种新的 ERSGs 评分系统，以预测患者的预后和 ICB 治疗的疗效。此外，我们确定 ZNF703 是 CRC 中 ICB 治疗的一个有前途的潜在靶点。
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