Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. To identify biologically relevant genes with prognostic and therapeutic significance in PDAC, we first performed the microarray gene-expression profiling in 45 matching pairs of tumor and adjacent non-tumor tissues from resected PDAC cases. We identified 36 genes that were associated with patient outcome and also differentially expressed in tumors as compared with adjacent non-tumor tissues in microarray analysis. Further evaluation in an independent validation cohort (N = 27) confirmed that DPEP1 (dipeptidase 1) expression was decreased (T: N ratio ∼0.1, P<0.01) in tumors as compared with non-tumor tissues. DPEP1 gene expression was negatively correlated with histological grade (Spearman correlation coefficient = −0.35, P = 0.004). Lower expression of DPEP1 in tumors was associated with poor survival (Kaplan Meier log rank) in both test cohort (P = 0.035) and validation cohort (P = 0.016). DPEP1 expression was independently associated with cancer-specific mortality when adjusted for tumor stage and resection margin status in both univariate (hazard ratio = 0.43, 95%CI = 0.24–0.76, P = 0.004) and multivariate analyses (hazard ratio = 0.51, 95%CI = 0.27–0.94, P = 0.032). We further demonstrated that overexpression of DPEP1 suppressed tumor cells invasiveness and increased sensitivity to chemotherapeutic agent Gemcitabine. Our data also showed that growth factor EGF treatment decreased DPEP1 expression and MEK1/2 inhibitor AZD6244 increased DPEP1 expression in vitro, indicating a potential mechanism for DPEP1 gene regulation. Therefore, we provide evidence that DPEP1 plays a role in pancreatic cancer aggressiveness and predicts outcome in patients with resected PDAC. In view of these findings, we propose that DPEP1 may be a candidate target in PDAC for designing improved treatments.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the United States and is among the most lethal human malignancies worldwide with a median survival of 6 months and 5-year survival of 6% [1]
We demonstrated that low DPEP1 expression is significantly associated with poor survival in the Germany test cohort and the Maryland validation cohort
Multivariate analysis showed that the association of DPEP1 with cancer-specific mortality was independent of resection margin status
Summary
PDAC is the fourth leading cause of cancer deaths in the United States and is among the most lethal human malignancies worldwide with a median survival of 6 months and 5-year survival of 6% [1]. An estimated 44,030 new cases and 37,660 deaths are expected to occur in the United States in 2011(American Cancer Society, Cancer Facts & Figures 2011). The median survival even for resected patients is less than 2 years with recurrence in ,80% of the cases within this time period. About 12% of the resected patients may survive for 5 years, which is attributed to the stage, grade and resection margin status and to the distinct biological makeup of tumors [2,3]
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