A positive feedback loop between hepatocyte growth factor receptor and β-catenin sustains colorectal cancer cell invasive growth

A. Rasola, M. Fassetta, F. De Bacco, L. D'Alessandro, D. Gramaglia, M. F. Di Renzo, P. M. Comoglio

Research output: Contribution to journalArticlepeer-review

Abstract

Overexpressed or activated hepatocyte growth factor receptor, encoded by the MET proto-oncogene, was found in the majority of colorectal carcinomas (CRCs), whose stepwise progression to malignancy requires transcriptional activation of β-catenin. We here demonstrate that a functional crosstalk between Met and β-catenin signaling sustains and increases CRC cell invasive properties. Hepatocyte growth factor (HGF) stimulation prompts β-catenin tyrosine phosphorylation and dissociation from Met, and upregulates β-catenin expression via the phosphatidylinositol 3-kinase pathway in conditions that mimic those found by the invading and metastasizing cells. Additionally, a transcriptionally active form of β-catenin, known to be oncogenic, enhances Met expression. Furthermore, HGF treatment increases the activity of the β-catenin-regulated T-cell factor transcription factor in cells expressing the wild-type or the oncogenic β-catenin. In the mirror experiments, either Met or β-catenin knocking down also reduces their protein level. In biological assays, β-catenin knocking down abrogates the HGF-induced motile phenotype, whereas active β-catenin fosters ligand-independent cell scattering. Met and β-catenin also cooperate in promoting entry into the cell cycle and in protecting cells from apoptosis. In conclusion, Met and β-catenin pathways are mutually activated in CRC cells. This might generate a self-amplifying positive feedback loop resulting in the upregulation of the invasive growth properties of CRC cells.

Original languageEnglish
Pages (from-to)1078-1087
Number of pages10
JournalOncogene
Volume26
Issue number7
DOIs
Publication statusPublished - Feb 15 2007

Keywords

  • β-catenin
  • Apoptosis
  • Colorectal carcinoma
  • Hepatocyte growth factor
  • Invasive growth

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Fingerprint

Dive into the research topics of 'A positive feedback loop between hepatocyte growth factor receptor and β-catenin sustains colorectal cancer cell invasive growth'. Together they form a unique fingerprint.

Cite this