Early Involvement of Death-Associated Protein Kinase Promoter Hypermethylation in the Carcinogenesis of Barrett's Esophageal Adenocarcinoma and Its Association with Clinical Progression

Abstract

Esophageal Barrett's adenocarcinoma (BA) develops through a multistage process, which is associated with the transcriptional silencing of tumor-suppressor genes by promoter CpG island hypermethylation. In this study, we explored the promoter hypermethylation and protein expression of proapoptotic death-associated protein kinase (DAPK) during the multistep Barrett's carcinogenesis cascade. Early BA and paired samples of premalignant lesions of 61 patients were analyzed by methylation-specific polymerase chain reaction and immunohistochemistry. For the association of clinicopathological markers and protein expression, an immunohistochemical tissue microarray analysis of 66 additional BAs of advanced tumor stages was performed. Hypermethylation of DAPK promoter was detected in 20% of normal mucosa, 50% of Barrett's metaplasia, 53% of dysplasia, and 60% of adenocarcinomas, and resulted in a marked decrease in DAPK protein expression (P < .01). The loss of DAPK protein was significantly associated with advanced depth of tumor invasion and advanced tumor stages (P < .001). Moreover, the severity of reflux esophagitis correlated significantly with the hypermethylation rate of the DAPK promoter (P < .003). Thus, we consider DAPK inactivation by promoter hypermethylation as an early event in Barrett's carcinogenesis and suggest that a decreased protein expression of DAPK likely plays a role in the development and progression of BA.

Inflammatory Cytokines IL-32 and IL-17 Have Common Signaling Intermediates despite Differential Dependence on TNF-Receptor 1

“…The second protein target identified for cytokines IL-32 and IL-17 in this study was DAPK-1, which is an apoptotic regulator and has been implicated in the disease process of several cancers (37)(38)(39). IL-32 is known to promote apoptosis of keratinocytes in atopic dermatitis (11), which supports our results that identified an apoptosis regulator, DAPK-1, as a protein target for IL-32.…”

Hypermethylation of multiple tumor-related genes associated with DMNT3b up-regulation served as a biomarker for early diagnosis of esophageal squamous cell carcinoma

“…As disruption of processes involved in programmed cell death is a common feature of human cancers, it is significant that inactivation of DAPK by promoter methylation has been described in esophageal cancer. [20][21][22] Retinoids regulate the growth, differentiation and apoptosis of premalignant and malignant cells during carcinogenesis. RAR-β, which acts as retinoic acid-dependent transcriptional activators, predominantly mediated the effects of retinoids.…”

DAPK-ZIPK-L13a Axis Constitutes a Negative-Feedback Module Regulating Inflammatory Gene Expression

“…DAPK has been implicated in occurrence and progression of several cancers. Hypermethylation of the DAPK promoter, accompanied by diminished transcription and mRNA expression, is strongly associated with non-small-cell lung cancer, Barrett’s esophageal adenocarcinoma, and chronic lymphocytic leukemia (Kim et al, 2001; Kuester et al, 2007; Raval et al, 2007). The mechanism by which diminished DAPK contributes to carcinogenesis is not known.…”