title: Further characterization of HDAC and SIRT gene expression patterns in pancreatic cancer and their relation to disease outcome.
abstract: Ductal adenocarcinoma of the pancreas is ranking 4 for patient' death from malignant disease in Western countries, with no satisfactory treatment. We re-examined more precisely the histone deacetylases (HDAC) and Sirtuin (SIRT) gene expression patterns in pancreatic cancer with more pancreatic tumors and normal tissues. We also examined the possible relationship between HDAC gene expression levels and long term disease outcome. Moreover, we have evaluated by using an in vitro model system of human pancreatic tumor cell line whether HDAC7 knockdown may affect the cell behavior. We analyzed 29 pancreatic adenocarcinoma (PA), 9 chronic pancreatitis (CP), 8 benign pancreatic (BP) and 11 normal pancreatic tissues. Concerning pancreatic adenocarcinoma, we were able to collect biopsies at the tumor periphery. To assess the possible involvement of HDAC7 in cell proliferation capacity, we have generated recombinant human Panc-1 tumor which underexpressed or overexpressed HDAC7. The expression of HDAC1,2,3,4,7 and Nur77 increased in PA samples at levels significantly higher than those observed in the CP group (p = 0.0160; 0.0114; 0.0227; 0.0440; 0.0136; 0.0004, respectively). The expression of HDAC7, was significantly greater in the PA compared with BP tissue samples (p = 0.05). Mean mRNA transcription levels of PA for HDAC7 and HDAC2 were higher when compared to their counterpart biopsies taken at the tumor periphery (p = 0.0346, 0.0053, respectively). Moreover, the data obtained using confocal microscopy and a quantitative method of immunofluorescence staining strongly support the HDAC7 overexpression in PA surgical specimens. The number of deaths and recurrences at the end of follow up were significantly greater in patients with overexpression of HDAC7. Interestingly, the rate of growth was significantly reduced in the case of cell carrying shRNA construct targeting HDAC7 encoding gene when compared to the parental Panc-1 tumor cells (p = 0.0015) at 48 h and 96 h (p = 0.0021). This study strongly support the notion that HDAC7play a role in pancreatic adenocarcinoma progression.
authors.affiliation: Aix-Marseille University, CRO2, UMR_S 911, Marseille, France; INSERM UMR 911, Marseille, France; AP-HM, Timone Hospital, Department of Digestive and visceral Surgery, Marseille, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Ouaïssi
authors.affiliation: Aix-Marseille University, CRO2, UMR_S 911, Marseille, France; INSERM UMR 911, Marseille, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Silvy
authors.affiliation: Aix-Marseille University, CRCM, UMR_S 1068, Institut Paoli-Calmettes, CNRS, UMR7258, Marseille, France; INSERM, UMR 1068, Marseille, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Loncle
authors.affiliation: Aix-Marseille University, CRO2, UMR_S 911, Marseille, France; INSERM UMR 911, Marseille, France; Faculdade de Farmácia da Universidade do Porto, Porto, Portugal.
authors.forename: Diva
authors.initials: D
authors.lastname: Ferraz da Silva
authors.affiliation: Aix-Marseille University, CRO2, UMR_S 911, Marseille, France; INSERM UMR 911, Marseille, France; Faculdade de Farmácia da Universidade do Porto, Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Martins Abreu
authors.affiliation: Aix-Marseille University, CRO2, UMR_S 911, Marseille, France; INSERM UMR 911, Marseille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Martinez
authors.affiliation: Aix-Marseille University, CRCM, UMR_S 1068, Institut Paoli-Calmettes, CNRS, UMR7258, Marseille, France; INSERM, UMR 1068, Marseille, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Berthézene
authors.affiliation: Aix-Marseille University, CRCM, UMR_S 1068, Institut Paoli-Calmettes, CNRS, UMR7258, Marseille, France; INSERM, UMR 1068, Marseille, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Cadra
authors.affiliation: AP-HM, La Conception Hospital, Department of hepatic transplantation and general surgery, Marseille, France; Aix-Marseille University, Marseille, France.
authors.forename: Yves Patrice
authors.initials: YP
authors.lastname: Le Treut
authors.affiliation: AP-HM, La Conception Hospital, Department of hepatic transplantation and general surgery, Marseille, France; Aix-Marseille University, Marseille, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Hardwigsen
authors.affiliation: Aix-Marseille University, CRO2, UMR_S 911, Marseille, France; INSERM UMR 911, Marseille, France; AP-HM, Timone Hospital, Department of Digestive and visceral Surgery, Marseille, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Sastre
authors.affiliation: AP-HM, Timone Hospital, Department of Digestive and visceral Surgery, Marseille, France; Aix-Marseille University, Marseille, France.
authors.forename: Igor
authors.initials: I
authors.lastname: Sielezneff
authors.affiliation: INSERM UMR 911, Marseille, France.
authors.forename: Liliane
authors.initials: L
authors.lastname: Benkoel
authors.affiliation: AP-HM, Timone Hospital, Department of histopathology, Marseille, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Delgrande
authors.affiliation: Faculdade de Farmácia da Universidade do Porto, Porto, Portugal.
authors.forename: Ali
authors.initials: A
authors.lastname: Ouaissi
authors.affiliation: Aix-Marseille University, CRCM, UMR_S 1068, Institut Paoli-Calmettes, CNRS, UMR7258, Marseille, France; INSERM, UMR 1068, Marseille, France.
authors.forename: Juan
authors.initials: J
authors.lastname: Iovanna
authors.affiliation: Aix-Marseille University, CRO2, UMR_S 911, Marseille, France; INSERM UMR 911, Marseille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Lombardo
authors.affiliation: Aix-Marseille University, CRO2, UMR_S 911, Marseille, France; INSERM UMR 911, Marseille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Mas
mesh_terms: D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002999:Clone Cells; D018572:Disease-Free Survival; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D050500:Pancreatitis, Chronic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D037761:Sirtuins / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D016896:Treatment Outcome
chemical_list: C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D037761:Sirtuins; C543273:HDAC7 protein, human; D006655:Histone Deacetylases