PMID- 28368395
OWN - NLM
STAT- MEDLINE
DCOM- 20170928
LR  - 20180512
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 36
IP  - 31
DP  - 2017 Aug
TI  - Mutant p53 upregulates alpha-1 antitrypsin expression and promotes invasion in
      lung cancer.
PG  - 4469-4480
LID - 10.1038/onc.2017.66 [doi]
AB  - 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.
FAU - Shakya, R
AU  - Shakya R
AD  - Centre for Personalised Cancer Medicine, Cancer Therapeutics Laboratory, School
      of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide,
      South Australia, Australia.
FAU - Tarulli, G A
AU  - Tarulli GA
AD  - Dame Roma Mitchell Cancer Research Laboratories (DRMCRL), School of Medicine,
      Faculty of Health Sciences, The University of Adelaide, Adelaide, South
      Australia, Australia.
FAU - Sheng, L
AU  - Sheng L
AD  - Centre for Personalised Cancer Medicine, Cancer Therapeutics Laboratory, School
      of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide,
      South Australia, Australia.
FAU - Lokman, N A
AU  - Lokman NA
AD  - Discipline of Obstetrics and Gynaecology, School of Medicine, Faculty of Health
      Sciences, Robinson Research Institute, The University of Adelaide, Adelaide,
      South Australia, Australia.
AD  - Adelaide Proteomics Centre, School of Molecular and Biological Sciences, The
      University of Adelaide, Adelaide, South Australia, Australia.
FAU - Ricciardelli, C
AU  - Ricciardelli C
AD  - Discipline of Obstetrics and Gynaecology, School of Medicine, Faculty of Health
      Sciences, Robinson Research Institute, The University of Adelaide, Adelaide,
      South Australia, Australia.
FAU - Pishas, K I
AU  - Pishas KI
AD  - Centre for Personalised Cancer Medicine, Cancer Therapeutics Laboratory, School
      of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide,
      South Australia, Australia.
FAU - Selinger, C I
AU  - Selinger CI
AD  - Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
FAU - Kohonen-Corish, M R J
AU  - Kohonen-Corish MRJ
AD  - The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New
      South Wales, Australia.
AD  - St Vincent's Clinical School, UNSW Australia, Sydney, New South Wales, Australia.
AD  - School of Medicine, University of Western Sydney, Parramatta, New South Wales,
      Australia.
FAU - Cooper, W A
AU  - Cooper WA
AD  - School of Medicine, University of Western Sydney, Parramatta, New South Wales,
      Australia.
AD  - Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital,
      Camperdown, New South Wales, Australia.
AD  - Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
FAU - Turner, A G
AU  - Turner AG
AD  - Centre for Personalised Cancer Medicine, Cancer Therapeutics Laboratory, School
      of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide,
      South Australia, Australia.
FAU - Neilsen, P M
AU  - Neilsen PM
AD  - Swinburne University of Technology Sarawak Campus, Kuching, Sarawak, Malaysia.
FAU - Callen, D F
AU  - Callen DF
AD  - Centre for Personalised Cancer Medicine, Cancer Therapeutics Laboratory, School
      of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide,
      South Australia, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170403
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (alpha 1-Antitrypsin)
SB  - IM
MH  - Cell Cycle
MH  - Cell Line, Tumor
MH  - Cell Movement
MH  - Epithelial-Mesenchymal Transition
MH  - Humans
MH  - Lung Neoplasms/*pathology
MH  - Mutation
MH  - Neoplasm Invasiveness
MH  - Proteomics
MH  - Tumor Suppressor Protein p53/*genetics/physiology
MH  - Up-Regulation
MH  - alpha 1-Antitrypsin/*genetics
EDAT- 2017/04/04 06:00
MHDA- 2017/09/29 06:00
CRDT- 2017/04/04 06:00
PHST- 2016/03/21 00:00 [received]
PHST- 2017/02/05 00:00 [revised]
PHST- 2017/02/05 00:00 [accepted]
PHST- 2017/04/04 06:00 [pubmed]
PHST- 2017/09/29 06:00 [medline]
PHST- 2017/04/04 06:00 [entrez]
AID - onc201766 [pii]
AID - 10.1038/onc.2017.66 [doi]
PST - ppublish
SO  - Oncogene. 2017 Aug;36(31):4469-4480. doi: 10.1038/onc.2017.66. Epub 2017 Apr 3.