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

Oncogene volume 26, pages 1078–1087 (2007)Cite this article

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.

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Acknowledgements

We thank Raffaella Albano, Laura Palmas and Solange Tienga for technical assistance. We are deeply indebted to Dr Federica Chiara, Dr Tiziana Venesio and Dr Daniela Cimino for helpful discussion, to Dr Ivan Dmitriev and Dr Damion Milne for the development and setup of the Image Analyzer software, and to our system operators Mario Belluardo, Antonino Ferraro, Andrea Carena and Paola Mantovani for inexhaustible support. Professor B Vogelstein gently provided the human β-catenin plasmid, Professor K Berns the β-catenin siRNAs, Dr S Corso the HGFR siRNAs and Dr G Nolan the Phoenix cell line.This work was supported by the Italian Ministry of Research and Education (FIRB/MIUR), by the Italian National Research Council (CNR – MIUR Progetto Oncologia) and by the Italian Association for Cancer Research (AIRC) funding to PMC and MFDR. AR and MF are recipient of Regione Piemonte Ricerca Scientifica Applicata fellowships. LDA is recipient of Italian Federation for Basic Research (FIRB) fellowship.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Università degli Studi di Padova, Padova, Italy

    A Rasola

  2. Division of Molecular Oncology, University of Torino Medical School, Candiolo, Italy

    A Rasola, M Fassetta, F De Bacco, L D'Alessandro, D Gramaglia & P M Comoglio

  3. Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo, Italy

    M F Di Renzo

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  1. A Rasola
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Correspondence to A Rasola.

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Rasola, A., Fassetta, M., De Bacco, F. et al. A positive feedback loop between hepatocyte growth factor receptor and β-catenin sustains colorectal cancer cell invasive growth. Oncogene 26, 1078–1087 (2007). https://doi.org/10.1038/sj.onc.1209859

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