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PMID: 19056927 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2.

Carcinogenesis ·Vol. 30 ·No. 2 ·2009-02-00 ·Pages 238-48

Gordon KJ, Kirkbride KC, How T, Blobe GC

Abstract

Bone morphogenetic proteins (BMPs) have an emerging role in human cancers. Here we demonstrate that the BMP-signaling pathway is intact and functional in human pancreatic cancer cells, with several BMP signaling components and transcriptional targets upregulated in human pancreatic cancer specimens compared with normal pancreatic tissue. Functionally, multiple BMP family members, including BMP-2, BMP-4 and BMP-7, induce an epithelial to mesenchymal transition (EMT) in the human pancreatic cancer cell line Panc-1, as demonstrated by morphological alterations and loss of E-cadherin expression. BMP-mediated EMT results in an increase in invasiveness of Panc-1 cells, in part through increased expression and activity of matrix metalloproteinase (MMP)-2, a known mediator of pancreatic cancer cell invasiveness. Accompanying EMT, BMP reduces expression of the transforming growth factor (TGF)-beta superfamily receptor, transforming growth factor-beta type III receptor (TbetaRIII), for which we have previously demonstrated loss of expression during pancreatic cancer progression. Maintaining TbetaRIII expression inhibits BMP-mediated invasion and suppresses Smad1 activation. Further, Smad1 is required for BMP-induced invasiveness and partially responsible for BMP-mediated increases in MMP-2 activity. These data suggest that BMP signaling, through Smad1 induction and upregulation of MMP-2, is an important mediator of pancreatic cancer invasiveness and a potential therapeutic target for treating this deadly disease.

MeSH Terms
Bone Morphogenetic Proteins/pharmacology,physiology Cell Differentiation/physiology Cell Line, Tumor Cell Movement/physiology Epithelial Cells/cytology,physiology Humans Matrix Metalloproteinase 2/metabolism Mesoderm/cytology,physiology Neoplasm Invasiveness Pancreatic Neoplasms/metabolism,pathology Proteoglycans/metabolism Receptors, Transforming Growth Factor beta/metabolism Signal Transduction/physiology Smad1 Protein/genetics,metabolism Up-Regulation
Chemicals
Bone Morphogenetic Proteins Proteoglycans Receptors, Transforming Growth Factor beta SMAD1 protein, human Smad1 Protein betaglycan Matrix Metalloproteinase 2
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Gordon Kelly J
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA.
Kirkbride Kellye C
How Tam
Blobe Gerard C
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Article Info
Journal
Carcinogenesis
Abbr.
Carcinogenesis
ISSN
1460-2180
DOI
10.1093/carcin/bgn274
Published
2009-02-00
Epub
2008-00-04
Pages
238-48
Language
English
Region
England
NLM ID
8008055
PMCID
PMC2639045
Subset
IM
Grants
NCI NIH HHS · CA106307 · United States
External Links
PubMed source DOI: 10.1093/carcin/bgn274 PMC Full Text View journal details
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