Expression of osteopontin, a target gene of de-regulated Wnt signaling, predicts survival in colon cancer

Int J Cancer. 2007 Oct 15;121(8):1717-23. doi: 10.1002/ijc.22868.

Abstract

Osteopontin (OPN) is a secreted phosphoprotein, which has been reported to be associated with tumor progression in numerous solid tumors. In a previous transcriptome study on colorectal cancer, we identified the gene OPN among the most strongly up-regulated transcripts. OPN has been suggested as a putative target of Wnt signaling, but the molecular mechanism responsible for its aberrant transcription is not fully understood. We analyzed 13 normal colon tissues, 9 adenomas, 120 primary colon tumors, and 10 liver metastases by quantitative reverse-transcription PCR. OPN expression was strongly elevated in primary colon cancer and liver metastasis, but not in pre-cancerous lesions and UICC stage I tumors. Multivariate analysis established OPN expression as an independent prognostic parameter for overall survival. Moreover, high OPN expression identified a subgroup of patients with bad prognosis. Next, we determined immunohistochemically a correlation of OPN expression with aberrant beta-catenin staining, which is indicative of Wnt activation. Elevated expression of OPN was significantly correlated with increased cytoplasmic and nuclear beta-catenin staining. The in vivo role of Wnt signaling for the expression of OPN was tested in genetically defined mouse models with (Apc(1638N)) or without (pvillin-KRAS(V12G)) Wnt activating mutations. Mutation of the tumor suppressor APC was necessary for upregulation of OPN expression in the murine tumors on transcript and on protein levels. Thus, OPN is a transcriptional target of aberrant Wnt signaling, and OPN expression alone predicts survival in human colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / chemistry
  • Adenoma / mortality
  • Aged
  • Animals
  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / genetics*
  • Colon / chemistry
  • Colonic Neoplasms / chemistry*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / mortality*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, APC
  • Humans
  • Liver Neoplasms / chemistry
  • Liver Neoplasms / mortality
  • Liver Neoplasms / secondary
  • Male
  • Mice
  • Middle Aged
  • Mutation
  • Osteopontin / analysis*
  • Osteopontin / genetics*
  • Precancerous Conditions / chemistry
  • Precancerous Conditions / mortality
  • Predictive Value of Tests
  • Prognosis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Survival Analysis
  • Up-Regulation
  • Wnt Proteins / genetics*
  • beta Catenin / analysis
  • beta Catenin / genetics

Substances

  • Biomarkers, Tumor
  • Wnt Proteins
  • beta Catenin
  • Osteopontin