title: Reduced expression of bone morphogenetic protein receptor IA in pancreatic cancer is associated with a poor prognosis.
abstract: BACKGROUND
  The expression of SMAD4, the central component of the transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling pathways, is lost in 50% of pancreatic cancers and is associated with a poor survival. Although the TGF-β pathway has been extensively studied and characterised in pancreatic cancer, there is very limited data on BMP signalling, a well-known tumour-suppressor pathway. BMP signalling can be lost not only at the level of SMAD4 but also at the level of BMP receptors (BMPRs), as has been described in colorectal cancer.
  
  
  METHODS
  We performed immunohistochemical analysis of the expression levels of BMP signalling components in pancreatic cancer and correlated these with survival. We also manipulated the activity of BMP signalling in vitro.
  
  
  RESULTS
  Reduced expression of BMPRIA is associated with a significantly worse survival, primarily in a subset of SMAD4-positive cancers. In vitro inactivation of SMAD4-dependent BMP signalling increases proliferation and invasion of pancreatic cancer cells, whereas inactivation of BMP signalling in SMAD4-negative cells does not change the proliferation and invasion or leads to an opposite effect.
  
  
  CONCLUSIONS
  Our data suggest that BMPRIA expression is a good prognostic marker and that the BMP pathway is a potential target for future therapeutic interventions in pancreatic cancer.
authors: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors: P W
authors: PW
authors: Voorneveld
authors: V
authors: V
authors: Stache
authors: R J
authors: RJ
authors: Jacobs
authors: E
authors: E
authors: Smolders
authors: A I
authors: AI
authors: Sitters
authors: A
authors: A
authors: Liesker
authors: K S
authors: KS
authors: Korkmaz
authors: S M
authors: SM
authors: Lam
authors: N F C C
authors: NF
authors: De Miranda
authors: H
authors: H
authors: Morreau
authors: L L
authors: LL
authors: Kodach
authors: J C H
authors: JC
authors: Hardwick
mesh_terms: D042683:Angiopoietin-1 / Q000096:biosynthesis; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000096:biosynthesis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D013534:Survival; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D014408:Biomarkers, Tumor; C554430:LDN 193189; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; C497796:SMAD4 protein, human; C481348:SPZ1 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I
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