Expression of the calcium-binding protein S100P is regulated by bone morphogenetic protein in pancreatic duct epithelial cell lines

Cancer Sci. 2009 Jan;100(1):103-10. doi: 10.1111/j.1349-7006.2008.00993.x. Epub 2008 Oct 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein 4 / pharmacology*
  • Calcium-Binding Proteins / genetics*
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Neoplasm Proteins / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Smad4 Protein / physiology


  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • Calcium-Binding Proteins
  • Neoplasm Proteins
  • S100P protein, human
  • SMAD4 protein, human
  • Smad4 Protein