title: 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.
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Geng
authors.initials: G
authors.lastname: Zhang
authors.forename: Aaron
authors.initials: A
authors.lastname: Schetter
authors.forename: Peijun
authors.initials: P
authors.lastname: He
authors.forename: Naotake
authors.initials: N
authors.lastname: Funamizu
authors.forename: Jochen
authors.initials: J
authors.lastname: Gaedcke
authors.forename: B Michael
authors.initials: BM
authors.lastname: Ghadimi
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: Raffit
authors.initials: R
authors.lastname: Hassan
authors.forename: Harris G
authors.initials: HG
authors.lastname: Yfantis
authors.forename: Dong H
authors.initials: DH
authors.lastname: Lee
authors.forename: Curtis
authors.initials: C
authors.lastname: Lacy
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Nader
authors.initials: N
authors.lastname: Hanna
authors.forename: H Richard
authors.initials: HR
authors.lastname: Alexander
authors.forename: S Perwez
authors.initials: SP
authors.lastname: Hussain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015331:Cohort Studies; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004150:Dipeptidases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056726:Genetic Association Studies; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008396:Maryland / Q000453:epidemiology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D058851:GPI-Linked Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C122167:TPX2 protein, human; D003841:Deoxycytidine; D004150:Dipeptidases; C549872:dipeptidase 1; D000093542:Gemcitabine