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Background <p>PERK (Protein kinase R-like endoplasmic reticulum kinase), encoded by <i>EIF2AK3</i>, is a key ER stress sensor that regulates protein synthesis and the unfolded protein response (UPR). Its dysregulation is linked to cancer development and progression. This study investigated <i>EIF2AK3</i>/PERK expression across 28 tumour types (<i>n</i> = 7,251) and their matched normal adjacent tissues (NATs; <i>n</i> = 667) from the Cancer Genome Atlas (TCGA) database, along with additional normal tissue samples from the Genotype-Tissue Expression (GTEx) project (<i>n</i> = 1,736), and 1,179 tumour cell lines, examining correlations with patient demographics, tumour stage, survival and genetic alterations.</p> Results <p>Transcriptomic analysis revealed <i>EIF2AK3</i> upregulation in multiple cancers, with proteomic data supporting increased PERK protein levels in specific tumour types. <i>EIF2AK3</i> expression was correlated with age, gender, tumour stage and survival endpoints in a context-dependent manner. Mutational analysis identified frequent <i>EIF2AK3</i> alterations, including missense, gain and amplification events. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the cell cycle, proteoglycans in cancer and focal adhesion pathways were among the most consistently enriched across tumour types, particularly in tumours with high <i>EIF2AK3</i> expression. These tumours also showed enrichment in Rap1 signalling, PI3K-Akt signalling, cytoskeletal regulation, ubiquitin-mediated proteolysis and nucleocytoplasmic transport, indicating a stress-adaptive invasive phenotype. In contrast, tumours with low <i>EIF2AK3</i> expression demonstrated enrichment in focal adhesion, AGE-RAGE signalling and cytoskeletal organisation, suggesting a tumour state dependent on adhesion integrity and extracellular matrix (ECM) interaction rather than stress-induced plasticity. Gene Ontology (GO) enrichment analysis supported these observations, with high <i>EIF2AK3</i> tumours displaying strong associations with cell adhesion, ECM structural remodelling and actin binding, while low <i>EIF2AK3</i> tumours showed enrichment in cytoskeletal stability and axonogenesis. Hierarchical clustering revealed a distinct gene cluster associated with <i>EIF2AK3</i> across several tumour types. Protein-protein interaction (PPI) and enrichment analyses linked this cluster to tumour progression and cell adhesion.</p> Conclusion <p>These findings underscore the central role of <i>EIF2AK3</i>/PERK in regulating cancer-associated pathways. Its expression stratifies tumours into biologically distinct phenotypes, with one favouring ER stress adaptation and invasiveness, and the other reliant on ECM organisation and adhesion homeostasis. <i>EIF2AK3</i> may thus serve as a potential therapeutic target in multiple cancers.</p>

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Pan-cancer analysis reveals differential PERK expression across tumour types and its potential as a therapeutic target

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Shivam Kumar,
  • Namshik Han,
  • Georgia Tsagkogeorga,
  • Murphy Lam Yim Wan

摘要

Background

PERK (Protein kinase R-like endoplasmic reticulum kinase), encoded by EIF2AK3, is a key ER stress sensor that regulates protein synthesis and the unfolded protein response (UPR). Its dysregulation is linked to cancer development and progression. This study investigated EIF2AK3/PERK expression across 28 tumour types (n = 7,251) and their matched normal adjacent tissues (NATs; n = 667) from the Cancer Genome Atlas (TCGA) database, along with additional normal tissue samples from the Genotype-Tissue Expression (GTEx) project (n = 1,736), and 1,179 tumour cell lines, examining correlations with patient demographics, tumour stage, survival and genetic alterations.

Results

Transcriptomic analysis revealed EIF2AK3 upregulation in multiple cancers, with proteomic data supporting increased PERK protein levels in specific tumour types. EIF2AK3 expression was correlated with age, gender, tumour stage and survival endpoints in a context-dependent manner. Mutational analysis identified frequent EIF2AK3 alterations, including missense, gain and amplification events. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the cell cycle, proteoglycans in cancer and focal adhesion pathways were among the most consistently enriched across tumour types, particularly in tumours with high EIF2AK3 expression. These tumours also showed enrichment in Rap1 signalling, PI3K-Akt signalling, cytoskeletal regulation, ubiquitin-mediated proteolysis and nucleocytoplasmic transport, indicating a stress-adaptive invasive phenotype. In contrast, tumours with low EIF2AK3 expression demonstrated enrichment in focal adhesion, AGE-RAGE signalling and cytoskeletal organisation, suggesting a tumour state dependent on adhesion integrity and extracellular matrix (ECM) interaction rather than stress-induced plasticity. Gene Ontology (GO) enrichment analysis supported these observations, with high EIF2AK3 tumours displaying strong associations with cell adhesion, ECM structural remodelling and actin binding, while low EIF2AK3 tumours showed enrichment in cytoskeletal stability and axonogenesis. Hierarchical clustering revealed a distinct gene cluster associated with EIF2AK3 across several tumour types. Protein-protein interaction (PPI) and enrichment analyses linked this cluster to tumour progression and cell adhesion.

Conclusion

These findings underscore the central role of EIF2AK3/PERK in regulating cancer-associated pathways. Its expression stratifies tumours into biologically distinct phenotypes, with one favouring ER stress adaptation and invasiveness, and the other reliant on ECM organisation and adhesion homeostasis. EIF2AK3 may thus serve as a potential therapeutic target in multiple cancers.