Reorganisation of Wnt-response pathways in colorectal tumorigenesis

Br J Cancer. 2008 Apr 22;98(8):1437-42. doi: 10.1038/sj.bjc.6604327. Epub 2008 Apr 15.

Abstract

In most colorectal tumours, APC mutation stabilises beta-catenin and mimics elements of Wnt growth factor signalling, but the high frequency of epigenetic loss of Wnt antagonists indicates an additional role for ligand-mediated Wnt signalling. Here, we have investigated the expression of key components of beta-catenin-independent Wnt response pathways to determine whether their profiles change during the transition from normal mucosa to colorectal adenomas. Transcription of the Wnt/planar cell polarity pathway determinant NKD1 (naked cuticle homologue 1) was induced in adenomas by a median 135-fold and in cancers by 7.4-fold. While some Frizzleds (FZDs) were downregulated in adenomas, the Wnt/Ca(2+) receptors FZD3 and FZD6 were induced by a median factor of 6.5 and 4.6, respectively. Naked cuticle homologue 1, FZD3 and FZD6 expression were coordinated in pre-malignant disease, but this relationship was lost in invasive cancers, where FZD induction was seen less frequently. Naked cuticle homologue 1 expression was associated with nuclear localisation of phospho-c-Jun in adenomas. In cultured cells, NKD1 transcription was induced by lithium chloride but FZD3 expression required Wnt growth factor treatment. These data show that Wnt responses are consistently directed towards both beta-catenin-independent routes in early colorectal tumorigenesis and elements of this are retained in more advanced cancers. These beta-catenin-independent Wnt signalling pathways may provide novel targets for chemoprevention of early colorectal tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / etiology
  • Adult
  • Aged
  • Aged, 80 and over
  • Calcium / metabolism
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics
  • Cell Line, Tumor
  • Colorectal Neoplasms / etiology*
  • Frizzled Receptors / biosynthesis
  • Frizzled Receptors / genetics
  • Humans
  • Middle Aged
  • Protein Kinase C / physiology
  • Receptors, G-Protein-Coupled / biosynthesis
  • Receptors, G-Protein-Coupled / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Wnt Proteins / physiology*
  • beta Catenin / physiology

Substances

  • Carrier Proteins
  • FZD3 protein, human
  • FZD6 protein, human
  • Frizzled Receptors
  • NKD1 protein, human
  • Receptors, G-Protein-Coupled
  • Wnt Proteins
  • beta Catenin
  • Protein Kinase C
  • Calcium