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DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma.

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.

SUBMITTER: Zhang G

PROVIDER: S-EPMC3282755 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma.

Zhang Geng G Schetter Aaron A He Peijun P Funamizu Naotake N Gaedcke Jochen J Ghadimi B Michael BM Ried Thomas T Hassan Raffit R Yfantis Harris G HG Lee Dong H DH Lacy Curtis C Maitra Anirban A Hanna Nader N Alexander H Richard HR Hussain S Perwez SP

PloS one 20120220 2

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 analysi ...[more]

PMID: 22363658

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Project description:Pancreatic ductal adenocarcinoma (PDA) is notorious for its poor prognosis. The current mainstay of treatment for PDA is surgical resection followed by adjuvant chemotherapy. However, it is difficult to predict the post-operative outcome because of the lack of reliable markers. The single-nucleotide polymorphism (SNP) of N-acetylgalactosaminyltransferase14 (GALNT14) has been proven to predict the progression-free survival (PFS), overall survival (OS) and response to chemotherapy in various types of gastrointestinal (GI) cancers. However, its role in PDA has not been studied. This study aims to investigate whether the GALNT14 SNP genotype can be a prognostic marker for PDA. A cohort of one hundred and three PDA patients having received surgical resection were retrospectively enrolled. GALNT14 genotypes and the clinicopathological parameters were correlated with postoperative prognosis. The genotype analysis revealed that 19.4%, 60.2% and 20.4% of patients had the GALNT14 "TT", "TG" and "GG" genotypes, respectively. The patients with the "GG" genotype had a mean OS time of 37.1 months (95% confidence interval [CI]: 18.2-56.1) and those with the "non-GG" genotype had a mean OS time of 16.1 months (95% CI: 13.1-19.2). Kaplan-Meier analysis showed that the "GG" genotype had a significantly better OS compared to the "non-GG" genotype (p = 0.005). However, there was no significant difference between the "GG" and "non-GG" genotypes in PFS (p = 0.172). The baseline characteristics between patients with the "GG" and "non-GG" genotypes were compared, and no significant difference was found. Univariate followed by multivariate Cox proportional hazard models demonstrated the GALNT14 "GG" genotype, negative resection margin, and locoregional disease as independent predictors for favorable OS (p = 0.003, p = 0.037, p = 0.021, respectively). Sensitivity analysis was performed in each subgroup to examine the relationship of GALNT14 with different clinicopathological variables and no heterogeneity was found. The GALNT14 "GG" genotype is associated with favorable survival outcome, especially OS, in patients with resected PDA and could serve as a prognostic marker.

Dataset Information

DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma.

Publications

DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma.

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