Carcinogenesis Advance Access originally published online on December 4, 2008
Carcinogenesis 2009 30(2):238-248; doi:10.1093/carcin/bgn274
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Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2
1 Department of Pharmacology and Cancer Biology
2 Department of Medicine, Duke University, Durham, NC 27708, USA
* To whom correspondence should be addressed. B354 Levine Science Research Center Research Drive, Box 91004, Durham, NC 27708, USA. Tel: +1 919 668 1352; Fax: +1 919 681 6906; Email: blobe001{at}mc.duke.edu
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)-β superfamily receptor, transforming growth factor-β type III receptor (TβRIII), for which we have previously demonstrated loss of expression during pancreatic cancer progression. Maintaining TβRIII 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.
Abbreviations: ALK, activin-receptor like kinase; BMP, bone morphogenetic protein; BMPR2, BMP type II receptor gene; EMT, epithelial to mesenchymal transition; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; HA, hemagglutinin; ID1, inhibitor of differentiation-1 gene; MMP, matrix metalloproteinase; MOI, multiplicity of infection; mRNA, messenger RNA; shRNA, short hairpin RNA; siRNA, small interfering RNA; TβRIII, transforming growth factor-β type III receptor; TGF, transforming growth factor
These authors contributed equally to this work. Received July 11, 2008; revised November 15, 2008; accepted November 29, 2008.