Abstract
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.
Highlights
The endoplasmic reticulum (ER) plays a pivotal role in the synthesis and proper folding of most proteins, including almost all secreted proteins (Oakes and Papa, 2015)
We investigated the potential functions of protein kinase R-like endoplasmic reticulum kinase (PERK) in certain cancers and found that PERK was significantly enriched in the immune-related signaling pathways in breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSC), and thyroid carcinoma (THCA), including B-cell differentiation, T-cell differentiation, T-cell activation, etc
We found that increased PERK expression correlates with poor prognosis and increased immune infiltration levels in B cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells of multiple cancers, especially in breast and thyroid cancers
Summary
The endoplasmic reticulum (ER) plays a pivotal role in the synthesis and proper folding of most proteins, including almost all secreted proteins (Oakes and Papa, 2015). UPR reaction is mainly mediated by three primary sensors: protein kinase R (PKR)-like endoplasmic reticulum kinase [PERK, known as eukaryotic initiation factor 2-alpha kinase 3 (EIF2AK3)], inositol-requiring gene 1 (IRE1), and activating transcription factor 6 (ATF6). Cancer cells usually invade into surrounding tissues The conditions in these environments are usually unfavorable (hypoxia, lack of glucose, lactic acidosis, oxidative stress, insufficient amino acid supply, etc.), which will hinder protein folding in the ER (Lee et al, 2003; Ma and Hendershot, 2004; Lee and Hendershot, 2006; Moenner et al, 2007). Many cancer cells have to overcome similar internal stresses, including oncogene activation, increased glycolysis, etc., which may cause overwhelming protein synthesis and a large demand for secretory pathways (Tollefsbol and Cohen, 1990; Ruggero, 2013; Dejeans et al, 2014). 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
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