title: Prolyl hydroxylase-2 (PHD2) exerts tumor-suppressive activity in pancreatic cancer.
abstract: BACKGROUND
  Pancreatic cancer is 1 of the most common and poorly treated tumors. In search of new therapeutic approaches, the oxygen sensors prolyl hydroxylases (PHD) are potential targets. PHD2 is considered the key oxygen sensor-regulating hypoxia-inducible factor (HIF). Currently, there is conflicting evidence regarding the exact role of PHD2 in tumorigenesis. The objective of this study was to investigate the role of PHD2 in pancreatic cancer growth and progression.
  
  
  METHODS
  PHD2 expression was analyzed by quantitative real-time polymerase chain reaction analysis and immunohistochemistry in human tissue specimens and cell lines. Knockdown of PHD2 was done by using short-interfering RNAs (siRNAs) specific against PHD2, and PHD2 overexpression was achieved by stable combinational DNA transfection. In vivo, an orthotopic murine model was used. Angiogenic cytokines were assessed with enzyme-linked immunosorbent assays, and invasion was studied with Matrigel assays.
  
  
  RESULTS
  PHD2 expression was not altered substantially in cancer tissues and their metastases. Lymph node-negative tissues had higher levels of PHD2 than lymph node-positive tissues. PHD2 was hypoxia-inducible in pancreatic cancer cell lines and regulated cell growth through cyclin D1 down-regulation samples with PHD2 suppression and through p21 up-regulation in samples with of PHD2 overexpression. In vivo, PHD2 caused tumor growth retardation and reduced tumor invasion by inhibiting angiogenesis. This observation was caused by the suppression of angiogenic cytokines and tumor invasion.
  
  
  CONCLUSIONS
  The current results indicated that PHD2 plays an important role in pancreatic tumorigenesis. In summary, the authors concluded that PHD2 may function as a tumor suppressor gene in pancreatic cancer and, thus, may define a potential target for the treatment of pancreatic cancer.
authors.affiliation: Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Yun
authors.initials: Y
authors.lastname: Su
authors.forename: Martin
authors.initials: M
authors.lastname: Loos
authors.forename: Natalia
authors.initials: N
authors.lastname: Giese
authors.forename: Eric
authors.initials: E
authors.lastname: Metzen
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.forename: Arno
authors.initials: A
authors.lastname: Kornberg
authors.forename: Peter
authors.initials: P
authors.lastname: Büchler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology*; D011393:Procollagen-Proline Dioxygenase / Q000502:physiology*; D012189:Retrospective Studies; D014183:Transplantation, Heterologous; D055815:Young Adult
chemical_list: D016207:Cytokines; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases