Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2
- 4 December 2008
- journal article
- Published by Oxford University Press (OUP) in Carcinogenesis: Integrative Cancer Research
- Vol. 30 (2), 238-248
- https://doi.org/10.1093/carcin/bgn274
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.Keywords
This publication has 45 references indexed in Scilit:
- Redox mechanisms switch on hypoxia-dependent epithelial–mesenchymal transition in cancer cellsCarcinogenesis: Integrative Cancer Research, 2008
- Pancreatic cancer biology and geneticsNature Reviews Cancer, 2002
- Bone Morphogenetic Protein-Mediating Receptor-Associated Smads as well as Common Smad Are Expressed in Human Articular Chondrocytes but not Up-Regulated or Down-Regulated in Osteoarthritic CartilageJournal of Bone and Mineral Research, 2002
- Signaling and transcriptional control of pancreatic organogenesisCurrent Opinion in Genetics & Development, 2002
- New functions for the matrix metalloproteinases in cancer progressionNature Reviews Cancer, 2002
- Expression of TGF-β Signaling Genes in the Normal, Premalignant, and Malignant Human Trophoblast: Loss of Smad3 in Choriocarcinoma CellsBiochemical and Biophysical Research Communications, 2001
- TGF-?-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator systemInternational Journal of Cancer, 2001
- Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation.2001
- Hormonal Regulation and Differential Actions of the Helix-Loop-Helix Transcriptional Inhibitors of Differentiation (Id1, Id2, Id3, and Id4) in Sertoli Cells*Endocrinology, 2001
- Expression of E-cadherin by human retinal pigment epithelium: delayed expression in vitro.1999