Table_7_The Prognostic Value of PERK in Cancer and Its Relationship With Immune Cell Infiltration.XLSX

Background: Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a type I transmembrane protein that functions as an endoplasmic reticulum (ER) stress sensor to regulate global protein synthesis. Recent research studies suggest that PERK, as an important receptor protein of unfolded protein response, is involved in the pathogenesis of many cancers. This study aimed to investigate PERK expression and its relationship with prognosis in pan-cancer and attempted to explore the relevant mechanism of PERK involved in the regulation of cancer pathogenesis.
Methods: The Oncomine and TIMER databases were used to analyze the expression of PERK between pan-cancer samples and normal samples. Survival analysis was performed using the PrognoScan, Kaplan–Meier (K-M) plotter, and UALCAN databases. Gene set enrichment analysis (GSEA) was used to perform the functional enrichment analysis of the PERK gene in breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSC), and thyroid carcinoma (THCA). The TIMER database was used to investigate the correlation between PERK expression and tumor-infiltrating immune cells and analyze the relationship of PERK with marker genes of immune cells which were downloaded from the CellMarker database in BRCA, HNSC, and THCA.
Results: PERK was differentially expressed in various cancers, such as breast cancer, liver cancer, lung cancer, gastric carcinoma, lymphoma, thyroid cancer, leukemia, and head and neck squamous cell carcinomas. The high expression of PERK was associated with a poor prognosis in KIRP, LGG, BRCA, and THCA and with a favorable prognosis in HNSC. The results of GSEA indicated that PERK was mainly enriched in immune-related signaling pathways in BRCA, HNSC, and THCA. Moreover, PERK expression was significant positively correlated with infiltrating levels of macrophages and dendritic cells and was strongly associated with a variety of immune markers, especially macrophage mannose receptor 1 (MRC1, also called CD206) and T-helper cells (Th).
Conclusion: The high expression of PERK could promote the infiltration of multiple immune cells in the tumor microenvironment and could deteriorate the outcomes of patients with breast and thyroid cancers, suggesting that PERK as well as tumor-infiltrating immune cells could be taken as potential biomarkers of prognosis.

背景：蛋白激酶R（Protein kinase R, PKR）样内质网激酶（PERK）是一种I型跨膜蛋白，可作为内质网（ER）应激感受器调控全局蛋白质合成。多项近期研究表明，作为未折叠蛋白反应的重要受体蛋白，PERK参与多种癌症的发生发展过程。本研究旨在探究PERK在泛癌中的表达水平及其与预后的关联，并试图揭示PERK参与调控癌症发生发展的相关机制。

方法：本研究借助Oncomine与TIMER数据库，分析泛癌样本与正常样本中PERK的表达差异。采用PrognoScan、凯普兰-迈耶（K-M）绘图器以及UALCAN数据库进行生存分析。采用基因集富集分析（GSEA）对乳腺浸润性癌（BRCA）、头颈部鳞状细胞癌（HNSC）以及甲状腺癌（THCA）中PERK基因进行功能富集分析。利用TIMER数据库探究PERK表达与肿瘤浸润免疫细胞的相关性，并分析PERK与从CellMarker数据库下载的BRCA、HNSC及THCA中免疫细胞标记基因的关联关系。

结果：PERK在乳腺癌、肝癌、肺癌、胃癌、淋巴瘤、甲状腺癌、白血病以及头颈部鳞状细胞癌等多种癌症中存在差异表达。PERK高表达与肾乳头状细胞癌（KIRP）、低级别胶质瘤（LGG）、BRCA以及THCA患者的不良预后相关，而与HNSC患者的良好预后相关。GSEA分析结果显示，在BRCA、HNSC及THCA中，PERK主要富集于免疫相关信号通路。此外，PERK表达水平与巨噬细胞、树突状细胞的浸润程度呈显著正相关，且与多种免疫标记物密切相关，尤其是巨噬细胞甘露糖受体1（MRC1，亦称CD206）与辅助性T细胞（Th）。

结论：PERK高表达可促进肿瘤微环境中多种免疫细胞的浸润，并会恶化乳腺癌与甲状腺癌患者的临床结局，这表明PERK与肿瘤浸润免疫细胞均可作为潜在的预后生物标志物。