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Mutant p53 upregulates alpha-1 antitrypsin expression and promotes invasion in lung cancer

Abstract

Missense mutations in the TP53 tumor-suppressor gene inactivate its antitumorigenic properties and endow the incipient cells with newly acquired oncogenic properties that drive invasion and metastasis. Although the oncogenic effect of mutant p53 transcriptome has been widely acknowledged, the global influence of mutant p53 on cancer cell proteome remains to be fully elucidated. Here, we show that mutant p53 drives the release of invasive extracellular factors (the ‘secretome’) that facilitates the invasion of lung cancer cell lines. Proteomic characterization of the secretome from mutant p53-inducible H1299 human non-small cell lung cancer cell line discovered that the mutant p53 drives its oncogenic pathways through modulating the gene expression of numerous targets that are subsequently secreted from the cells. Of these genes, alpha-1 antitrypsin (A1AT) was identified as a critical effector of mutant p53 that drives invasion in vitro and in vivo, together with induction of epithelial–mesenchymal transition markers expression. Mutant p53 upregulated A1AT transcriptionally through the involvement with its family member p63. Conditioned medium containing secreted A1AT enhanced cell invasion, while an A1AT-blocking antibody attenuated the mutant p53-driven migration and invasion. Importantly, high A1AT expression correlated with increased tumor stage, elevated p53 staining and shorter overall survival in lung adenocarcinoma patients. Collectively, these findings suggest that A1AT is an indispensable target of mutant p53 with prognostic and therapeutic potential in mutant p53-expressing tumors.

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Acknowledgements

We thank TCGA research network for publicly sharing their data. The results published here are in part based upon data generated by the TCGA project, which was established by the NCI and NHGRI. Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov. We also thank Rebecca C Haycox for her technical assistance. This work was supported by the NHMRC Project grants (44107714 and 44112162). K Pishas acknowledges financial contributions from the University of Adelaide Florey Medical Research Foundation Clinical Cancer Research Fellowship.

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Correspondence to R Shakya.

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Shakya, R., Tarulli, G., Sheng, L. et al. Mutant p53 upregulates alpha-1 antitrypsin expression and promotes invasion in lung cancer. Oncogene 36, 4469–4480 (2017). https://doi.org/10.1038/onc.2017.66

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