title: 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.
authors.affiliation: Centre for Personalised Cancer Medicine, Cancer Therapeutics Laboratory, School of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Shakya
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories (DRMCRL), School of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: G A
authors.initials: GA
authors.lastname: Tarulli
authors.affiliation: Centre for Personalised Cancer Medicine, Cancer Therapeutics Laboratory, School of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Sheng
authors.affiliation: Discipline of Obstetrics and Gynaecology, School of Medicine, Faculty of Health Sciences, Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.|Adelaide Proteomics Centre, School of Molecular and Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: N A
authors.initials: NA
authors.lastname: Lokman
authors.affiliation: Discipline of Obstetrics and Gynaecology, School of Medicine, Faculty of Health Sciences, Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Ricciardelli
authors.affiliation: Centre for Personalised Cancer Medicine, Cancer Therapeutics Laboratory, School of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: K I
authors.initials: KI
authors.lastname: Pishas
authors.affiliation: Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: C I
authors.initials: CI
authors.lastname: Selinger
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.|St Vincent's Clinical School, UNSW Australia, Sydney, New South Wales, Australia.|School of Medicine, University of Western Sydney, Parramatta, New South Wales, Australia.
authors.forename: M R J
authors.initials: MRJ
authors.lastname: Kohonen-Corish
authors.affiliation: School of Medicine, University of Western Sydney, Parramatta, New South Wales, Australia.|Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: W A
authors.initials: WA
authors.lastname: Cooper
authors.affiliation: Centre for Personalised Cancer Medicine, Cancer Therapeutics Laboratory, School of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: A G
authors.initials: AG
authors.lastname: Turner
authors.affiliation: Swinburne University of Technology Sarawak Campus, Kuching, Sarawak, Malaysia.
authors.forename: P M
authors.initials: PM
authors.lastname: Neilsen
authors.affiliation: Centre for Personalised Cancer Medicine, Cancer Therapeutics Laboratory, School of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: D F
authors.initials: DF
authors.lastname: Callen
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D009154:Mutation; D009361:Neoplasm Invasiveness; D040901:Proteomics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation; D000515:alpha 1-Antitrypsin / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000515:alpha 1-Antitrypsin