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

Bone morphogenetic proteins (BMPs) have an emerging role inhuman cancers. Here we demonstrate that the BMP-signaling pathwayis intact and functional in human pancreatic cancer cells, withseveral BMP signaling components and transcriptional targetsupregulated in human pancreatic cancer specimens compared withnormal pancreatic tissue. Functionally, multiple BMP familymembers, including BMP-2, BMP-4 and BMP-7, induce an epithelialto mesenchymal transition (EMT) in the human pancreatic cancercell line Panc-1, as demonstrated by morphological alterationsand loss of E-cadherin expression. BMP-mediated EMT resultsin an increase in invasiveness of Panc-1 cells, in part throughincreased expression and activity of matrix metalloproteinase(MMP)-2, a known mediator of pancreatic cancer cell invasiveness.Accompanying EMT, BMP reduces expression of the transforminggrowth factor (TGF)-β superfamily receptor, transforminggrowth factor-β type III receptor (TβRIII), for whichwe have previously demonstrated loss of expression during pancreaticcancer progression. Maintaining TβRIII expression inhibitsBMP-mediated invasion and suppresses Smad1 activation. Further,Smad1 is required for BMP-induced invasiveness and partiallyresponsible for BMP-mediated increases in MMP-2 activity. Thesedata suggest that BMP signaling, through Smad1 induction andupregulation of MMP-2, is an important mediator of pancreaticcancer invasiveness and a potential therapeutic target for treatingthis 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