Aims: To reveal the prognostic role of unfolded protein response (UPR) -related genes in hepatocellular carcinoma (HCC). Background: Hepatocellular carcinoma is a genetically heterogeneous tumor, and the prediction of its prognosis remains a challenge. Studies elucidating the molecular mechanisms of UPR have rapidly increased. However, the UPR molecular subtype characteristics of the related genes in HCC progression have yet to be thoroughly studied. Objective: Conducting a comprehensive assessment of the prognostic signature of genes related to the UPR in patients with HCC can advance our understanding of the cellular processes contributing to the progression of HCC and offer innovative strategies in precise therapy. Method: Based on the gene expression profiles associated with UPR in HCC, we explored the molecular subtypes mediated by UPR-related genes and constructed a UPR-related genes signature that could precisely predict the prognosis for HCC. Result: Using microarray data of HCC patients, differentially expressed UPR-related genes (DEGs) were discovered in malignancies and normal tissues. The HCC was classified into two molecular subtypes by the NMF algorithm based on DEGs modification of the UPR. Moreover, we developed a UPR-related model for predicting HCC patients' prognosis. The robustness of the UPR- related model was confirmed in external validation. Moreover, we analyzed immune responses in different risk groups. Analysis of immune functions revealed that Treg, Macrophages, aDCs, and MHC class-I were significantly up-regulated in high-risk HCC. At the same time, cytolytic activity and type I and II INF response were higher in a low-risk subgroup. Conclusion: This study identified two UPR molecular subtypes of HCC and developed a ten-gene HCC prognostic signature model (EXTL3, PPP2R5B, ZBTB17, CCT3, CCT4, CCT5, GRPEL2, HSP90AA1, PDRG1, and STC2), which can robustly forecast the progression of HCC.

中文翻译：

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未折叠蛋白反应相关基因在肝细胞癌中的预后作用

目的：揭示未折叠蛋白反应（UPR）相关基因在肝细胞癌（HCC）中的预后作用。背景：肝细胞癌是一种遗传异质性肿瘤，其预后的预测仍然是一个挑战。阐明 UPR 分子机制的研究迅速增加。然而，HCC进展相关基因的UPR分子亚型特征仍有待深入研究。目的：对 HCC 患者 UPR 相关基因的预后特征进行全面评估，可以增进我们对 HCC 进展的细胞过程的理解，并为精准治疗提供创新策略。方法：基于HCC中与UPR相关的基因表达谱，我们探索了UPR相关基因介导的分子亚型，并构建了可以精确预测HCC预后的UPR相关基因特征。结果：利用 HCC 患者的微阵列数据，在恶性肿瘤和正常组织中发现了差异表达的 UPR 相关基因（DEG）。基于UPR的DEGs修饰的NMF算法将HCC分为两种分子亚型。此外，我们开发了一个 UPR 相关模型来预测 HCC 患者的预后。UPR相关模型的稳健性在外部验证中得到了证实。此外，我们分析了不同风险群体的免疫反应。免疫功能分析显示，高危肝癌中 Treg、巨噬细胞、aDC 和 MHC I 类显着上调。同时，低风险亚组的细胞溶解活性以及 I 型和 II 型 INF 反应较高。结论：本研究确定了 HCC 的两种 UPR 分子亚型，并开发了十基因 HCC 预后特征模型（EXTL3、PPP2R5B、ZBTB17、CCT3、CCT4、CCT5、GRPEL2、HSP90AA1、PDRG1 和 STC2），该模型可以稳健地预测进展肝癌。