MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial.
Apoptosis
Cell Cycle Proteins
Cell Line, Tumor
Cell Proliferation
DNA Methylation
Hepatocyte Growth Factor
/ genetics
Hippo Signaling Pathway
Humans
Lung Neoplasms
/ drug therapy
Mesothelioma
/ drug therapy
Mesothelioma, Malignant
Neoplasm Invasiveness
Nuclear Proteins
/ metabolism
Pleural Neoplasms
/ drug therapy
Promoter Regions, Genetic
Protein Serine-Threonine Kinases
/ genetics
Proto-Oncogene Proteins
/ genetics
Transcription Factors
/ metabolism
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
05
09
2018
accepted:
20
12
2018
revised:
15
12
2018
pubmed:
12
2
2019
medline:
31
10
2019
entrez:
12
2
2019
Statut:
ppublish
Résumé
The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed-cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation. Promoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines. STK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09-2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines. MST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.
Sections du résumé
BACKGROUND
The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed-cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation.
METHODS
Promoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines.
RESULTS
STK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09-2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines.
CONCLUSIONS
MST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.
Identifiants
pubmed: 30739911
doi: 10.1038/s41416-019-0379-8
pii: 10.1038/s41416-019-0379-8
pmc: PMC6461894
doi:
Substances chimiques
Cell Cycle Proteins
0
Nuclear Proteins
0
Proto-Oncogene Proteins
0
Transcription Factors
0
YY1AP1 protein, human
0
macrophage stimulating protein
0
Hepatocyte Growth Factor
67256-21-7
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
387-397Références
J Thorac Oncol. 2015 May;10(5):844-51
pubmed: 25902174
Oncogene. 2002 Jun 20;21(27):4340-4
pubmed: 12082623
Genes (Basel). 2016 Jun 17;7(6):
pubmed: 27322327
Cell Res. 2016 Jul;26(7):805-21
pubmed: 27174051
J Thorac Oncol. 2012 Mar;7(3):599-606
pubmed: 22246193
Nat Genet. 2016 Apr;48(4):407-16
pubmed: 26928227
Curr Biol. 2008 Mar 11;18(5):311-21
pubmed: 18328708
EMBO J. 2009 May 6;28(9):1319-31
pubmed: 19339990
Acta Biochim Biophys Sin (Shanghai). 2013 Apr;45(4):268-79
pubmed: 23419720
Lung Cancer. 2006 Oct;54(1):109-16
pubmed: 16893590
Transl Lung Cancer Res. 2017 Jun;6(3):335-342
pubmed: 28713678
Pathol Int. 2011 Jun;61(6):331-44
pubmed: 21615608
Oncol Rep. 2009 Dec;22(6):1519-26
pubmed: 19885608
Genes Dev. 2016 Jan 1;30(1):1-17
pubmed: 26728553
Clin Cancer Res. 2012 May 15;18(10):2976-86
pubmed: 22434665
Cancer Res. 2016 Mar 15;76(6):1627-40
pubmed: 26759237
Tumour Biol. 2013 Oct;34(5):3239-43
pubmed: 23737290
Lancet. 2016 Apr 2;387(10026):1405-1414
pubmed: 26719230
Clin Cancer Res. 2016 Mar 1;22(5):1256-64
pubmed: 26459179
Cell Signal. 2017 Aug;36:163-175
pubmed: 28487119
Clin Cancer Res. 2017 Jun 15;23(12):3191-3202
pubmed: 28003305
Am J Cancer Res. 2015 Dec 15;6(1):27-37
pubmed: 27073720
Cell Biosci. 2013 Aug 28;3(1):31
pubmed: 23985272
J Cell Mol Med. 2017 Nov;21(11):2663-2676
pubmed: 28470935
Biochem Biophys Res Commun. 2015 Aug 7;463(4):968-74
pubmed: 26056943
Curr Biol. 2009 Apr 28;19(8):675-81
pubmed: 19327996
Curr Biol. 2009 Nov 3;19(20):1692-702
pubmed: 19836237
Curr Biol. 2007 Apr 17;17(8):700-5
pubmed: 17379520
Mol Carcinog. 2007 Oct;46(10):865-71
pubmed: 17538946
J Immunol. 2016 Sep 1;197(5):1683-91
pubmed: 27465533
Sci Rep. 2017 Mar 22;7:45020
pubmed: 28327630
Sci Rep. 2017 Oct 27;7(1):14265
pubmed: 29079854
Cancer Gene Ther. 2013 Aug;20(8):453-60
pubmed: 23928732
Int J Oncol. 2014 Aug;45(2):853-60
pubmed: 24841766
J Biol Chem. 2011 Feb 25;286(8):6253-61
pubmed: 21199877
Br J Ind Med. 1960 Oct;17:260-71
pubmed: 13782506
Cancer Res. 2006 Mar 1;66(5):2562-9
pubmed: 16510573
Biochemistry. 2016 Oct 4;55(39):5507-5519
pubmed: 27618557
Stem Cell Res. 2017 Apr;20:42-49
pubmed: 28257933