Yes-associated protein (YAP) induces a secretome phenotype and transcriptionally regulates plasminogen activator Inhibitor-1 (PAI-1) expression in hepatocarcinogenesis.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Carcinogenesis
/ genetics
Carcinoma, Hepatocellular
/ genetics
Cell Line, Tumor
Cellular Senescence
/ genetics
DNA-Binding Proteins
/ metabolism
Disease Models, Animal
Gene Expression Regulation, Neoplastic
Hepatocytes
/ metabolism
Liver Neoplasms
/ genetics
Mice, Transgenic
Muscle Proteins
/ metabolism
Phenotype
Plasminogen Activator Inhibitor 1
/ genetics
Prognosis
Promoter Regions, Genetic
/ genetics
Proteome
/ metabolism
TEA Domain Transcription Factors
Transcription Factors
/ metabolism
Transcription, Genetic
YAP-Signaling Proteins
Hepatocellular carcinoma
Hippo pathway
Liver cancer
Oncogene
Transcriptional regulator
Journal
Cell communication and signaling : CCS
ISSN: 1478-811X
Titre abrégé: Cell Commun Signal
Pays: England
ID NLM: 101170464
Informations de publication
Date de publication:
23 10 2020
23 10 2020
Historique:
received:
10
03
2020
accepted:
31
07
2020
entrez:
24
10
2020
pubmed:
25
10
2020
medline:
12
8
2021
Statut:
epublish
Résumé
Overexpression and nuclear enrichment of the oncogene yes-associated protein (YAP) cause tumor initiation and support tumor progression in human hepatocellular carcinoma (HCC) via cell autonomous mechanisms. However, how YAP expression in tumor cells affects intercellular communication within the tumor microenvironment is not well understood. To investigate how tumor cell-derived YAP is changing the paracrine communication network between tumor cells and non-neoplastic cells in hepatocarcinogenesis, the expression and secretion of cytokines, growth factors and chemokines were analyzed in transgenic mice with liver-specific and inducible expression of constitutively active YAP (YAP YAP overexpression induced the expression and secretion of many paracrine-acting factors with potential impact on tumorous or non-neoplastic cells (e.g. plasminogen activator inhibitor-1 (PAI-1), C-X-C motif chemokine ligand 13 (CXCL13), CXCL16). Expression analyses of human HCC patients showed an overexpression of PAI-1 in human HCC tissues and a correlation with poor overall survival as well as early cancer recurrence. PAI-1 statistically correlated with genes typically induced by YAP, such as connective tissue growth factor (CTGF) and cysteine rich angiogenic inducer 61 (CYR61) or YAP-dependent gene signatures (CIN4/25). In vitro, YAP inhibition diminished the expression and secretion of PAI-1 in murine and human liver cancer cell lines. PAI-1 affected the expression of genes involved in cellular senescence and oncogene-induced senescence was confirmed in YAP These results demonstrate that the oncogene YAP changes the secretome response of hepatocytes and hepatocyte-derived tumor cells. In this context, the secreted protein PAI-1 is transcriptionally regulated by YAP in hepatocarcinogenesis. Perturbation of these YAP-dependent communication hubs including PAI-1 may represent a promising pharmacological approach in tumors with YAP overexpression. Video abstract.
Sections du résumé
BACKGROUND
Overexpression and nuclear enrichment of the oncogene yes-associated protein (YAP) cause tumor initiation and support tumor progression in human hepatocellular carcinoma (HCC) via cell autonomous mechanisms. However, how YAP expression in tumor cells affects intercellular communication within the tumor microenvironment is not well understood.
METHODS
To investigate how tumor cell-derived YAP is changing the paracrine communication network between tumor cells and non-neoplastic cells in hepatocarcinogenesis, the expression and secretion of cytokines, growth factors and chemokines were analyzed in transgenic mice with liver-specific and inducible expression of constitutively active YAP (YAP
RESULTS
YAP overexpression induced the expression and secretion of many paracrine-acting factors with potential impact on tumorous or non-neoplastic cells (e.g. plasminogen activator inhibitor-1 (PAI-1), C-X-C motif chemokine ligand 13 (CXCL13), CXCL16). Expression analyses of human HCC patients showed an overexpression of PAI-1 in human HCC tissues and a correlation with poor overall survival as well as early cancer recurrence. PAI-1 statistically correlated with genes typically induced by YAP, such as connective tissue growth factor (CTGF) and cysteine rich angiogenic inducer 61 (CYR61) or YAP-dependent gene signatures (CIN4/25). In vitro, YAP inhibition diminished the expression and secretion of PAI-1 in murine and human liver cancer cell lines. PAI-1 affected the expression of genes involved in cellular senescence and oncogene-induced senescence was confirmed in YAP
CONCLUSIONS
These results demonstrate that the oncogene YAP changes the secretome response of hepatocytes and hepatocyte-derived tumor cells. In this context, the secreted protein PAI-1 is transcriptionally regulated by YAP in hepatocarcinogenesis. Perturbation of these YAP-dependent communication hubs including PAI-1 may represent a promising pharmacological approach in tumors with YAP overexpression. Video abstract.
Identifiants
pubmed: 33097058
doi: 10.1186/s12964-020-00634-6
pii: 10.1186/s12964-020-00634-6
pmc: PMC7583285
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
DNA-Binding Proteins
0
Muscle Proteins
0
Plasminogen Activator Inhibitor 1
0
Proteome
0
TEA Domain Transcription Factors
0
TEAD4 protein, human
0
Transcription Factors
0
YAP-Signaling Proteins
0
Yap1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
166Références
J Cell Sci. 2013 Jan 15;126(Pt 2):508-20
pubmed: 23230145
Gastroenterology. 2013 Jun;144(7):1530-1542.e12
pubmed: 23419361
Gastroenterology. 2017 Jun;152(8):2037-2051.e22
pubmed: 28249813
Nucleic Acids Res. 2014 Jan;42(Database issue):D142-7
pubmed: 24194598
PLoS Biol. 2005 Apr;3(4):e113
pubmed: 15799695
Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1431-6
pubmed: 20080598
Cell Oncol (Dordr). 2019 Feb;42(1):93-106
pubmed: 30456574
Cell Rep. 2018 Nov 20;25(8):2177-2191.e7
pubmed: 30463014
Nat Rev Mol Cell Biol. 2007 Sep;8(9):729-40
pubmed: 17667954
Trends Cancer. 2019 May;5(5):297-307
pubmed: 31174842
Thromb Res. 2009 Sep;124(4):403-8
pubmed: 19351570
J Pharmacol Sci. 2018 Oct;138(2):89-95
pubmed: 30340922
Annu Rev Pathol. 2010;5:99-118
pubmed: 20078217
Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
pubmed: 12184808
J Biol Chem. 2007 Mar 23;282(12):9288-96
pubmed: 17276980
Hepatology. 2008 Jul;48(1):146-56
pubmed: 18537183
Gastroenterology. 2017 Feb;152(3):533-545
pubmed: 28003097
Nature. 2017 Jun 22;546(7659):533-538
pubmed: 28614297
Proc Natl Acad Sci U S A. 2010 May 4;107(18):8248-53
pubmed: 20404163
Nat Rev Drug Discov. 2014 Jan;13(1):63-79
pubmed: 24336504
Cancer Lett. 2020 Mar 31;473:164-175
pubmed: 31904487
Cancer Res. 2010 Dec 15;70(24):10202-12
pubmed: 21159642
Biomed Res Int. 2015;2015:345413
pubmed: 26161394
Nature. 2012 Sep 6;489(7414):57-74
pubmed: 22955616
Nat Cell Biol. 2006 Aug;8(8):877-84
pubmed: 16862142
Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):E3402-11
pubmed: 26080399
Cancer Metastasis Rev. 2019 Sep;38(3):483-492
pubmed: 31734763
Am J Physiol Lung Cell Mol Physiol. 2015 Feb 15;308(4):L344-57
pubmed: 25502501
Genes Dev. 2008 Jul 15;22(14):1962-71
pubmed: 18579750
Mol Cell. 2005 May 13;18(4):447-59
pubmed: 15893728
Cell Rep. 2020 Jun 23;31(12):107809
pubmed: 32579935
J Clin Invest. 1993 Dec;92(6):2756-60
pubmed: 8254029
Genes Dev. 2012 Jun 15;26(12):1300-5
pubmed: 22677547
Biomed Pharmacother. 2018 Sep;105:83-94
pubmed: 29852393
Carcinogenesis. 2008 Apr;29(4):824-9
pubmed: 18258607
Eur J Med Chem. 2015 Mar 6;92:619-36
pubmed: 25615797
Arterioscler Thromb Vasc Biol. 2013 May;33(5):935-42
pubmed: 23471233
Cancer Cell. 2017 Mar 13;31(3):355-367
pubmed: 28238683
Curr Biol. 2007 Dec 4;17(23):2054-60
pubmed: 17980593