The loss of CASP4 expression is associated with poor prognosis in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) has high biological malignant potential among the various digestive tract cancers and is associated with a poor prognosis. To identify novel genes involved in tumor progression, the present study analyzed the genetic and transcriptional alterations in two clinical cohorts, totaling 157 cases of ESCC (78 cases from the discovery set and 79 cases from the validation set). From the discovery set, gene expression and copy number profiles were analyzed using expression arrays and array-comparative genomic hybridization, respectively. Notably, a copy number loss of caspase-4 (CASP4) was observed in 82% of ESCC cases and CASP4 expression levels were significantly associated with copy number levels. Gene set enrichment analysis demonstrated that the upregulation of CASP4 expression levels was associated with the signaling pathways involved in apoptosis, inflammatory responses and immune responses. The present study demonstrated that CASP4 expression levels were significantly associated with the expression levels of the endoplasmic reticulum (ER) stress marker glucose-regulated protein 78, indicating that CASP4 has a role in cell death induced by ER stress in ESCC. In the survival analysis the CASP4 low expression group exhibited a poor prognosis, compared with the CASP4 high expression group in the discovery set (P=0.003); this observation was reproduced in the validation set (P=0.037). Therefore, the results of the current study suggest that CASP4 may function as a tumor-suppressor gene and may have applications as a biomarker for the prediction of the prognosis in ESCC.