Expression of the calcium-binding protein S100P is regulated by bone morphogenetic protein in pancreatic duct epithelial cell lines.
We previously reported that bone morphogenetic protein (BMP)-4 induces epithelial-mesenchymal transition in a pancreatic cancer cell line. To further investigate the detailed molecular mechanism of BMP action in pancreatic cancer, we carried out comprehensive microarray analysis in Panc-1 cells. The microarray analysis elucidated novel BMP target genes, and among them, the calcium-binding protein S100P was identified as an upregulated gene. S100P induction by BMP4 was confirmed by real-time reverse transcription-polymerase chain reaction and western blot analysis in Panc-1 and HPDE cells. Short interfering RNA-based knockdown of S100P expression sufficiently repressed BMP4-induced cell migration in Panc-1 cells. Because Panc-1 and HPDE cells express wild-type Smad4, we hypothesized that Smad4 might be indispensable for S100P induction by BMP4. S100P induction by BMP4 was not observed in the Smad4-null cell line BxPC3, and was sufficiently attenuated in short interfering RNA-based Smad4-knockdown Panc-1 cells. Interestingly, detailed promoter analysis revealed that upregulation of S100P by BMP4 was independent of the Smad-binding element, indicating that an additional unknown downstream factor of the Smad4-dependent pathway is necessary for this induction. These findings are the first of their kind, and this Smad4-dependent regulation of S100P by BMP signaling might explain the migratory mechanism of cancer cells, which is still unknown.
Hamada
Shin
S
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.
Satoh
Kennichi
K
Hirota
Morihisa
M
Fujibuchi
Wataru
W
Kanno
Atsushi
A
Umino
Jun
J
Ito
Hiromichi
H
Satoh
Akihiko
A
Kikuta
Kazuhiro
K
Kume
Kiyoshi
K
Masamune
Atsushi
A
Shimosegawa
Tooru
T
D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051901:Smad4 Protein / Q000502:physiology
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D002135:Calcium-Binding Proteins; D009363:Neoplasm Proteins; C103003:S100P protein, human; C497796:SMAD4 protein, human; D051901:Smad4 Protein