Bone morphogenetic protein 4 induces epithelial-mesenchymal transition through MSX2 induction on pancreatic cancer cell line.
In our study, we found that bone morphogenetic protein 4 (BMP4) has a novel effect as an inducer of epithelial-mesenchymal transition (EMT) on Panc-1 cells, a human pancreatic carcinoma cell line. BMP4-treated Panc-1 cells showed loose cell contacts and a scattered, fibroblast-like appearance along with E-cadherin downregulation, Vimentin upregulation and enhanced cell migration, which are characteristic of EMT. BMP4 treatment also induced homeobox gene MSX2 expression, which we previously showed to be associated with EMT in pancreatic carcinoma cells. BMP4 treatment activated the Smad signaling pathway, and extracellular signal-related kinase (ERK) and p38 mitogen-activated kinase (MAPK) pathways in these cells. MSX2 was markedly induced by BMP4 through the ERK and p38 MAPK pathways in collaboration with the Smad signaling pathway. The repression of E-cadherin, induction of Vimentin and enhanced cell migration disappeared when siRNA-based MSX2 downregulated pancreatic cancer cells were treated with BMP4. These findings indicate that BMP4 may be involved in pancreatic carcinoma development through the promotion of EMT and that MSX2 is indispensable to this process.
Hamada
Shin
S
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Satoh
Kennichi
K
Hirota
Morihisa
M
Kimura
Kenji
K
Kanno
Atsushi
A
Masamune
Atsushi
A
Shimosegawa
Tooru
T
D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004848:Epithelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005452:Fluoresceins / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005456:Fluorescent Dyes / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008648:Mesoderm / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011419:Propidium / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014746:Vimentin / Q000378:metabolism
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D015820:Cadherins; D004268:DNA-Binding Proteins; D005452:Fluoresceins; D005456:Fluorescent Dyes; D018398:Homeodomain Proteins; C084119:MSX2 protein; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014746:Vimentin; D011419:Propidium