∆133p53 isoform promotes tumour invasion and metastasis via interleukin-6 activation of JAK-STAT and RhoA-ROCK signalling

Hamish Campbell, Nicholas Fleming, Imogen Roth, Sunali Mehta, Anna Wiles, Gail Williams, Claire Vennin, Nikola Arsic, Ashleigh Parkin, Marina Pajic, Fran Munro, Les McNoe, Michael Black, John McCall, Tania L. Slatter, Paul Timpson, Roger Reddel, Pierre Roux, Cristin Print, Margaret A. Baird and Antony W. Braithwaite ()
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Hamish Campbell: University of Sydney
Nicholas Fleming: University of Otago
Imogen Roth: University of Otago
Sunali Mehta: University of Otago
Anna Wiles: University of Otago
Gail Williams: University of Otago
Claire Vennin: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Nikola Arsic: Centre de Recherche de Biochimie Macromoléculaire de Montpellier
Ashleigh Parkin: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Marina Pajic: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Fran Munro: University of Otago
Les McNoe: University of Otago
Michael Black: University of Otago
John McCall: University of Otago
Tania L. Slatter: University of Otago
Paul Timpson: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Roger Reddel: University of Sydney
Pierre Roux: Centre de Recherche de Biochimie Macromoléculaire de Montpellier
Cristin Print: c/o The University of Auckland
Margaret A. Baird: University of Otago
Antony W. Braithwaite: University of Sydney

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract ∆122p53 mice (a model of ∆133p53 isoform) are tumour-prone, have extensive inflammation and elevated serum IL-6. To investigate the role of IL-6 we crossed ∆122p53 mice with IL-6 null mice. Here we show that loss of IL-6 reduced JAK-STAT signalling, tumour incidence and metastasis. We also show that ∆122p53 activates RhoA-ROCK signalling leading to tumour cell invasion, which is IL-6-dependent and can be reduced by inhibition of JAK-STAT and RhoA-ROCK pathways. Similarly, we show that Δ133p53 activates these pathways, resulting in invasive and migratory phenotypes in colorectal cancer cells. Gene expression analysis of colorectal tumours showed enrichment of GPCR signalling associated with ∆133TP53 mRNA. Patients with elevated ∆133TP53 mRNA levels had a shorter disease-free survival. Our results suggest that ∆133p53 promotes tumour invasion by activation of the JAK-STAT and RhoA-ROCK pathways, and that patients whose tumours have high ∆133TP53 may benefit from therapies targeting these pathways.

Date: 2018
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DOI: 10.1038/s41467-017-02408-0

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