Prospero-related homeobox 1 (PROX1) is frequently inactivated by genomic deletions and epigenetic silencing in carcinomas of the bilary system

J Hepatol. 2007 Jan;46(1):89-97. doi: 10.1016/j.jhep.2006.07.033. Epub 2006 Sep 27.

Abstract

Background/aims: Functional deletion of the transcription factor Prospero-related homeobox 1 (PROX1) causes abnormal cellular proliferation via down-regulated expression of the cell cycle inhibitors p27(kip1) and p57(kip2). Hence, we examined whether inactivation of the PROX1 gene can be demonstrated in malignant tumors of the bilary system.

Methods: Seventeen paraffin-embedded specimens of carcinomas of the bilary system were subjected to loss-of-heterozygosity (LOH) and microsatellite instability analyses, methylation-specific polymerase-chain reaction (MSP) and immunohistochemical detection of PROX1 protein in tumor sections.

Results: The marker D1S213 located close to PROX1 at 1q41 indicated LOH events in 50% of informative tumor samples analyzed. In contrast to intense cytoplasmic and nuclear staining of normal bile duct epithelia, PROX1 protein was absent or drastically reduced in 10 of 16 (63%) carcinomas. MSP revealed significant PROX1 promoter hypermethylation in 8 out of 17 clinical cases (47%). A correlation between clinicopathological characteristics and reduced PROX1 expression was not observed.

Conclusions: We demonstrate that mechanisms like genomic deletions and hypermethylation, which are prototypic for the inactivation of tumor suppressor genes, inactivate PROX1 in carcinomas of the bilary system. Our findings prompt the elucidation of molecular pathways involved in PROX1 dependent misregulation of differentiation and proliferation processes in bilary tract carcinomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Biliary Tract Neoplasms / genetics*
  • Biliary Tract Neoplasms / metabolism
  • Biliary Tract Neoplasms / pathology
  • Chromosomes, Human, Pair 1 / genetics
  • DNA Methylation
  • DNA, Neoplasm / genetics
  • Epigenesis, Genetic*
  • Female
  • Gene Deletion*
  • Gene Silencing*
  • Genes, Homeobox
  • Genes, Tumor Suppressor
  • Homeodomain Proteins / antagonists & inhibitors*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Loss of Heterozygosity
  • Male
  • Microsatellite Instability
  • Middle Aged
  • Tumor Suppressor Proteins

Substances

  • DNA, Neoplasm
  • Homeodomain Proteins
  • Tumor Suppressor Proteins
  • prospero-related homeobox 1 protein