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The Δ133p53 isoform and its mouse analogue Δ122p53 promote invasion and metastasis involving pro-inflammatory molecules interleukin-6 and CCL2

Oncogene volume 35, pages 4981–4989 (2016)Cite this article

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Abstract

A number of naturally occurring isoforms of the tumour suppressor protein p53 have been discovered, which appear to have differing roles in tumour prevention or promotion. We are investigating the tumour-promoting activities of the Δ133p53 isoform using our mouse model of Δ133p53 (Δ122p53). Here, we report that tumours from Δ122p53 homozygous mice show evidence of invasion and metastasis and that Δ122p53 promotes migration though a 3-dimensional collagen matrix. We also show that Δ122p53 and Δ133p53 promote cell migration in scratch wound and Transwell assays, similar to the ‘gain-of-function’ phenotypes seen with mutant p53. Using the well-defined B16 mouse melanoma metastatic model, we show that Δ122p53 leads to faster generation of lung metastases. The increased migratory phenotypes are dependent on secreted factors, including the cytokine interleukin-6 and the chemokine CCL2. We propose that Δ122p53 (and Δ133p53) acts in a similar manner to ‘gain-of-function’ mutant p53 proteins to promote migration, invasion and metastasis, which may contribute to poor survival in patients with Δ133p53-expressing tumours.

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Abbreviations

FBS:

foetal bovine serum

FL:

full-length

IL-6:

interleukin-6

MEF:

mouse embryonic fibroblast

PDAC:

pancreatic ductal adenocarcinoma

TP53:

human p53 gene

WT:

wild type

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Acknowledgements

This work was supported by the Health Research Council of New Zealand, Marsden Fund, Maurice Wilkins Centre for Molecular Biodiscovery, Cancer Council NSW and National Health and Medical Research Council.

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Author notes

  1. I Roth and H Campbell: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    I Roth, M Wilson, A Wiles, G Williams, A Woolley, N Fleming, M Baird & A W Braithwaite

  2. Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, University of Auckland, Auckland, New Zealand

    I Roth, M Baird & A W Braithwaite

  3. Children’s Medical Research Institute, University of Sydney, Sydney, New South Wales, Australia

    H Campbell, C Rubio & A W Braithwaite

  4. The Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    C Vennin & P Timpson

  5. Malaghan Institute for Medical Research, Wellington, New Zealand

    M V Berridge

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Correspondence to A W Braithwaite.

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Roth, I., Campbell, H., Rubio, C. et al. The Δ133p53 isoform and its mouse analogue Δ122p53 promote invasion and metastasis involving pro-inflammatory molecules interleukin-6 and CCL2. Oncogene 35, 4981–4989 (2016). https://doi.org/10.1038/onc.2016.45

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  • DOI: https://doi.org/10.1038/onc.2016.45

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