DNA hypermethylation of nonspecific cytotoxic cell receptor protein 1 and poor prognosis of pancreatic cancer.

Pancreatic cancer (PC) is a highly fatal malignancy and one of the leading causes of cancer-related deaths globally. Pancreatitis and inflammation-induced epigenetic changes, such as DNA methylation, have been reported to be involved in carcinogenesis and progression of PC. The present study examined the precise expression and DNA methylation status of nonspecific cytotoxic cell receptor protein 1 (NCCRP1), identified as a methylation target gene in esophageal cancers, in paired adjacent normal pancreas and PC tissues. NCCRP1 expression was immunohistochemically analyzed using formalin-fixed, paraffin-embedded sections of 73 patients with PC who underwent surgery. The DNA methylation status was analyzed in 52 paired adjacent normal and PC tissues using pyrosequencing. In normal pancreatic tissues, NCCRP1 expression was restricted to acinar cells and absent in ductal and islet cells. Most PCs (64/73) showed a loss of NCCRP1 expression, whereas NCCRP1 expression was observed in 9 cases. Among the NCCRP1-positive cases, 8 (89%) were classified as anaplastic carcinoma, an undifferentiated subtype of PC. When human PC cell lines were treated with 5-aza-2'-deoxycytidine, a DNA-methyltransferase inhibitor, NCCRP1 transcription was induced. Pyrosequencing analysis revealed that the promoter regions of NCCRP1 were highly DNA methylated in PC tissues compared with paired adjacent normal tissues. Furthermore, PC cases with DNA hypermethylated (>18.88%) NCCRP1 exhibited significantly poorer survival than those with relatively low levels of NCCRP1 methylation (P=0.0164). The data collectively suggested that NCCRP1 expression was frequently lost in PC, likely due to promoter hypermethylation, resulting in poor prognosis. This indicates the potential of NCCRP1 as a diagnostic and prognostic biomarker and a therapeutic target for patients with PC.