title: Expression of the calcium-binding protein S100P is regulated by bone morphogenetic protein in pancreatic duct epithelial cell lines.
abstract: 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.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Hamada
authors.forename: Kennichi
authors.initials: K
authors.lastname: Satoh
authors.forename: Morihisa
authors.initials: M
authors.lastname: Hirota
authors.forename: Wataru
authors.initials: W
authors.lastname: Fujibuchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kanno
authors.forename: Jun
authors.initials: J
authors.lastname: Umino
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ito
authors.forename: Akihiko
authors.initials: A
authors.lastname: Satoh
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kikuta
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kume
authors.forename: Atsushi
authors.initials: A
authors.lastname: Masamune
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: 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
chemical_list: 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