Further Characterization of HDAC and SIRT Gene Expression Patterns in Pancreatic Cancer and Their Relation to Disease Outcome

Mehdi Ouaissi (1) , Françoise Silvy (1) , Céline Loncle (2) , Diva Ferraz da Silva (1) , Carla Martins Abreu (1) , Emmanuelle Martinez (1) , Patrick Berthézene (2) , Sophie Cadra (2) , Yves Patrice Le Treut (3) , Jean Hardwigsen (3) , Bernard Sastre (1) , Igor Sielezneff (4) , Liliane Benkoel (1) , Jean Delgrande (4) , Ali Ouaissi (5) , Juan Iovanna (2) , Dominique Lombardo (1) , Eric Mas (1)

1 CRO2 - Centre de Recherches en Oncologie biologique et Oncopharmacologie
2 CRCM - Centre de Recherche en Cancérologie de Marseille
3 LA CONCEPTION - Hôpital de la Conception [CHU - APHM]
4 TIMONE - Hôpital de la Timone [CHU - APHM]
5 FFUP - Faculdade de Farmácia da Universidade do Porto

Ductal adenocarcinoma of the pancreas is ranking 4 for patient' death from malignant disease in Western countries, with no satisfactory treatment. We reexamined more precisely the histone deacetylases (HDAC) and Sirtuin (SIRT) gene expression patterns in pancreatic cancer with more pancreatic tumors and normal tissues. We also examinedthe 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.

Mots clés: Gene expression; Adenocarcinomas; Cloning; Pancreatic cancer; Surgical and invasive medical procedures; Surgical oncology; Biopsy; Apoptosis

Domaines: Cancer; Hépatologie et Gastroentérologie; Génomique, Transcriptomique et Protéomique [q-bio.GN]

Mehdi Ouaissi, Françoise Silvy, Céline Loncle, Diva Ferraz da Silva, Carla Martins Abreu, et al.. Further Characterization of HDAC and SIRT Gene Expression Patterns in Pancreatic Cancer and Their Relation to Disease Outcome. PLoS ONE, 2014, 9 (10), pp.e108520. ⟨10.1371/journal.pone.0108520⟩. ⟨hal-01772514⟩