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

Shakya, R; Tarulli, GA; Sheng, L; Lokman, NA; Ricciardelli, C; Pishas, KI; Selinger, CI; Kohonen-Corish, MRJ; Cooper, WA; Turner, AG; Neilsen, PM; Callen, DF

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

Shakya, R Tarulli, GA Sheng, L Lokman, NA Ricciardelli, C Pishas, KI Selinger, CI Kohonen-Corish, MRJ Cooper, WA Turner, AG Neilsen, PM Callen, DF

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Publisher:: Springer Nature [academic journals on nature.com]
Publication Type:: Journal Article
Citation:: Oncogene, 2017, 36, (31), pp. 4469-4480
Issue Date:: 2017-08

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Field	Value	Language
dc.contributor.author	Shakya, R
dc.contributor.author	Tarulli, GA
dc.contributor.author	Sheng, L
dc.contributor.author	Lokman, NA
dc.contributor.author	Ricciardelli, C
dc.contributor.author	Pishas, KI
dc.contributor.author	Selinger, CI
dc.contributor.author	Kohonen-Corish, MRJ
dc.contributor.author	Cooper, WA
dc.contributor.author	Turner, AG
dc.contributor.author	Neilsen, PM
dc.contributor.author	Callen, DF
dc.date.accessioned	2022-09-13T04:45:04Z
dc.date.available	2017-02-05
dc.date.available	2022-09-13T04:45:04Z
dc.date.issued	2017-08
dc.identifier.citation	Oncogene, 2017, 36, (31), pp. 4469-4480
dc.identifier.issn	0950-9232
dc.identifier.issn	1476-5594
dc.identifier.uri	http://hdl.handle.net/10453/161781
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Springer Nature [academic journals on nature.com]
dc.relation.ispartof	Oncogene
dc.relation.isbasedon	10.1038/onc.2017.66
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1103 Clinical Sciences, 1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	alpha 1-Antitrypsin
dc.subject.mesh	Cell Cycle
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cell Movement
dc.subject.mesh	Epithelial-Mesenchymal Transition
dc.subject.mesh	Humans
dc.subject.mesh	Lung Neoplasms
dc.subject.mesh	Mutation
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	Proteomics
dc.subject.mesh	Tumor Suppressor Protein p53
dc.subject.mesh	Up-Regulation
dc.subject.mesh	Cell Cycle
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cell Movement
dc.subject.mesh	Epithelial-Mesenchymal Transition
dc.subject.mesh	Humans
dc.subject.mesh	Lung Neoplasms
dc.subject.mesh	Mutation
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	Proteomics
dc.subject.mesh	Tumor Suppressor Protein p53
dc.subject.mesh	Up-Regulation
dc.subject.mesh	alpha 1-Antitrypsin
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Humans
dc.subject.mesh	Lung Neoplasms
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	alpha 1-Antitrypsin
dc.subject.mesh	Proteomics
dc.subject.mesh	Cell Cycle
dc.subject.mesh	Cell Movement
dc.subject.mesh	Up-Regulation
dc.subject.mesh	Mutation
dc.subject.mesh	Tumor Suppressor Protein p53
dc.subject.mesh	Epithelial-Mesenchymal Transition
dc.title	Mutant p53 upregulates alpha-1 antitrypsin expression and promotes invasion in lung cancer.
dc.type	Journal Article
utslib.citation.volume	36
utslib.location.activity	England
utslib.for	1103 Clinical Sciences
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-09-13T04:45:00Z
pubs.issue	31
pubs.publication-status	Published
pubs.volume	36
utslib.citation.issue	31

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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http://hdl.handle.net/10453/161781