Format

Send to

Choose Destination
Nat Commun. 2018 Jan 17;9(1):254. doi: 10.1038/s41467-017-02408-0.

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

Author information

1
Children's Medical Research Institute, University of Sydney, Sydney, NSW, 2145, Australia.
2
Department of Pathology, Dunedin School of Medicine, University of Otago, 56 Hanover Street, 9054, Dunedin, New Zealand.
3
Maurice Wilkins Centre for Molecular Biodiscovery, University of Otago, c/o The University of Auckland, Private Bag 92019, 1142 Auckland, New Zealand.
4
The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, NSW, 2010, Australia.
5
Faculty of Medicine, St Vincent's Clinical School, 370 Victoria St, Darlinghurst, NSW, 2010, Australia.
6
CNRS, Centre de Recherche de Biochimie Macromoléculaire de Montpellier, 1919 Route de Mende, 34293, Montpellier, France.
7
Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, 201 Great King St, 9054, Dunedin, New Zealand.
8
Department of Biochemistry, School of Biomedical Sciences, University of Otago, 710 Cumberland St, 9054, Dunedin, New Zealand.
9
Department of Molecular Medicine and Pathology, Faculty of Medicine, The University of Auckland, Private Bag 92019, 1142, Auckland, New Zealand.
10
Bioinformatics Institute, University of Auckland, Private Bag 92019, 1142, Auckland, New Zealand.
11
Children's Medical Research Institute, University of Sydney, Sydney, NSW, 2145, Australia. antony.braithwaite@otago.ac.nz.
12
Department of Pathology, Dunedin School of Medicine, University of Otago, 56 Hanover Street, 9054, Dunedin, New Zealand. antony.braithwaite@otago.ac.nz.
13
Maurice Wilkins Centre for Molecular Biodiscovery, University of Otago, c/o The University of Auckland, Private Bag 92019, 1142 Auckland, New Zealand. antony.braithwaite@otago.ac.nz.

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.

PMID:
29343721
PMCID:
PMC5772473
DOI:
10.1038/s41467-017-02408-0
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center