Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT116 cells

Exp Cell Res. 2007 Mar 10;313(5):1033-44. doi: 10.1016/j.yexcr.2006.12.020. Epub 2007 Jan 10.

Abstract

Bone morphogenetic protein (BMP), a member of the TGF-beta superfamily, is involved in development, morphogenesis, cell proliferation and apoptosis. Dysregulation of BMP signaling has been suggested in tumorigenesis. In an analysis of human colon normal mucosa and tumors at different stages by immunohistochemistry, we observed that the intensity of BMP-4 staining in late-adenocarcinomas was stronger than that in normal mucosa and adenomas, while there was no difference in the staining of its receptors (BMPR-IA and BMPR-II) at all stages. The up-regulation of BMP-4 was further validated in another panel of tumor tissues by real-time RT-PCR, showing that BMP-4 mRNA levels in primary colonic carcinomas with liver metastasis were significantly higher than that in the matched normal mucosa. In order to understand the functional relevance of BMP-4 expression in colon cancer progression, BMP-4-overexpressing cell clones were generated from HCT116 cells. Overexpression of BMP-4 did not affect the HCT116 cell growth. The cells overexpressing BMP-4 became resistant to serum-starvation-induced apoptosis and exhibited enhanced migration and invasion characteristics. Overexpression of BMP-4 changed cell morphology to invasive spindle phenotype and induced the expression and activity of urokinase plasminogen activator (uPA). These results indicate that BMP-4 confers invasive phenotype during progression of colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Apoptosis
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Protein Receptors, Type I / metabolism
  • Bone Morphogenetic Protein Receptors, Type II / metabolism
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Movement*
  • Cell Survival
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Computer Systems
  • Humans
  • Immunohistochemistry
  • Intestinal Mucosa / metabolism*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / secondary*
  • Polymerase Chain Reaction
  • Protein Array Analysis
  • RNA, Messenger / metabolism
  • Transfection
  • Up-Regulation
  • Urokinase-Type Plasminogen Activator / metabolism

Substances

  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins
  • RNA, Messenger
  • Bone Morphogenetic Protein Receptors, Type I
  • Bone Morphogenetic Protein Receptors, Type II
  • Urokinase-Type Plasminogen Activator