1. ¹Department of Biomedical Sciences, Università degli Studi di Padova, Padova, Italy
2. ²Division of Molecular Oncology, University of Torino Medical School, Candiolo, Italy
3. ³Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo, Italy

Correspondence: Dr A Rasola, Department of Biomedical Sciences, Università degli Studi di Padova, viale Giuseppe Colombo 3, I-35121 Padova, Italy. E-mail: rasola@bio.unipd.it

Received 26 January 2006; Revised 27 June 2006; Accepted 28 June 2006; Published online 4 September 2006.

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 -catenin. We here demonstrate that a functional crosstalk between Met and -catenin signaling sustains and increases CRC cell invasive properties. Hepatocyte growth factor (HGF) stimulation prompts -catenin tyrosine phosphorylation and dissociation from Met, and upregulates -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 -catenin, known to be oncogenic, enhances Met expression. Furthermore, HGF treatment increases the activity of the -catenin-regulated T-cell factor transcription factor in cells expressing the wild-type or the oncogenic -catenin. In the mirror experiments, either Met or -catenin knocking down also reduces their protein level. In biological assays, -catenin knocking down abrogates the HGF-induced motile phenotype, whereas active -catenin fosters ligand-independent cell scattering. Met and -catenin also cooperate in promoting entry into the cell cycle and in protecting cells from apoptosis. In conclusion, Met and -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.