Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer.
Boolean networks
cofilin-1
modeling
molecular mechanism
pancreatic cancer
predicting therapeutic targets
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
10 Feb 2021
10 Feb 2021
Historique:
received:
05
01
2021
revised:
26
01
2021
accepted:
07
02
2021
entrez:
13
2
2021
pubmed:
14
2
2021
medline:
14
2
2021
Statut:
epublish
Résumé
Cofilin-1 (CFL1) overexpression in pancreatic cancer correlates with high invasiveness and shorter survival. Besides a well-documented role in actin remodeling, additional cellular functions of CFL1 remain poorly understood. Here, we unraveled molecular tumor-promoting functions of CFL1 in pancreatic cancer. For this purpose, we first show that a knockdown of CFL1 results in reduced growth and proliferation rates in vitro and in vivo, while apoptosis is not induced. By mechanistic modeling we were able to predict the underlying regulation. Model simulations indicate that an imbalance in actin remodeling induces overexpression and activation of CFL1 by acting on transcription factor 7-like 2 (TCF7L2) and aurora kinase A (AURKA). Moreover, we could predict that CFL1 impacts proliferation and apoptosis via the signal transducer and activator of transcription 3 (STAT3). These initial model-based regulations could be substantiated by studying protein levels in pancreatic cancer cell lines and human datasets. Finally, we identified the surface protein CD44 as a promising therapeutic target for pancreatic cancer patients with high CFL1 expression.
Identifiants
pubmed: 33578795
pii: cancers13040725
doi: 10.3390/cancers13040725
pmc: PMC7916621
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : FP7 Ideas: European Research Council
ID : 602783
Organisme : Deutsche Forschungsgemeinschaft
ID : SFB 1074 project Z1
Organisme : Deutsche Forschungsgemeinschaft
ID : GRK 2254 HEIST
Organisme : Bundesministerium für Bildung und Forschung
ID : Forschungskern SyStaR
Organisme : Bundesministerium für Bildung und Forschung
ID : e:Med, SYMBOL-HF
Organisme : Bundesministerium für Bildung und Forschung
ID : e:Med, conFim
Organisme : Deutsche Forschungsgemeinschaft
ID : Clinical Research Unit 325, subproject A2
Références
PLoS One. 2014 Feb 28;9(2):e90371
pubmed: 24587343
Cell Death Dis. 2015 Oct 29;6:e1955
pubmed: 26512963
PLoS One. 2014 Apr 16;9(4):e93046
pubmed: 24740004
Cell. 1994 Nov 18;79(4):573-82
pubmed: 7954824
Cell Mol Life Sci. 2013 Feb;70(4):661-87
pubmed: 22864622
Front Physiol. 2018 Apr 24;9:431
pubmed: 29740342
Exp Cell Res. 2006 Feb 15;312(4):468-77
pubmed: 16337627
Cancer Invest. 2013 Feb;31(2):132-9
pubmed: 23320827
Cancer Res. 1997 Mar 15;57(6):1206-12
pubmed: 9067294
EMBO J. 2005 Feb 9;24(3):473-86
pubmed: 15660133
Hum Pathol. 2008 Feb;39(2):251-8
pubmed: 17959228
Bioinformatics. 2017 Feb 15;33(4):601-604
pubmed: 27797768
J Cell Biol. 2006 May 8;173(3):395-404
pubmed: 16651380
Cancer Lett. 2013 May 28;332(2):346-58
pubmed: 21078544
J Biol Chem. 2011 Sep 30;286(39):34254-61
pubmed: 21832093
Trends Biochem Sci. 2008 Aug;33(8):394-403
pubmed: 18639460
Cancer Sci. 2017 Apr;108(4):795-803
pubmed: 28161904
Mol Biol Cell. 2010 Oct 15;21(20):3529-39
pubmed: 20739464
Mol Cancer. 2003 Jan 07;2:6
pubmed: 12605713
Gastroenterology. 2009 Jul;137(1):361-71, 371.e1-5
pubmed: 19362090
Exp Mol Pathol. 2005 Dec;79(3):187-93
pubmed: 16229833
Clin Cancer Res. 2004 Apr 15;10(8):2846-50
pubmed: 15102693
Int J Oncol. 2016 Mar;48(3):908-18
pubmed: 26781210
Nat Cell Biol. 2009 May;11(5):545-56
pubmed: 19329994
Cell Cycle. 2009 Aug;8(15):2365-74
pubmed: 19556892
J Biol Chem. 2004 Feb 20;279(8):7193-8
pubmed: 14645219
Mol Cancer Res. 2011 Dec;9(12):1573-86
pubmed: 21970856
Cancers (Basel). 2019 Jan 23;11(2):
pubmed: 30678127
Cancer Res. 2014 Apr 15;74(8):2362-73
pubmed: 24509905
J Clin Invest. 2012 Mar;122(3):859-72
pubmed: 22307329
Oncotarget. 2016 Oct 25;7(43):70881-70897
pubmed: 27765920
Cancer Lett. 2016 Feb 1;371(1):79-89
pubmed: 26616283
Cancer Cell. 2013 Mar 18;23(3):406-20
pubmed: 23453624
J Neurochem. 2012 Feb;120(4):515-27
pubmed: 22117609
Biochim Biophys Acta. 2007 Aug;1773(8):1299-310
pubmed: 17188374
Gastroenterology. 2020 Sep;159(3):1019-1035.e22
pubmed: 32446697
Cell. 1997 Nov 14;91(4):479-89
pubmed: 9390557
Gastroenterology. 2011 Aug;141(2):719-30, 730.e1-7
pubmed: 21684285
Oncotarget. 2017 Sep 6;8(54):92043-92054
pubmed: 29190896
J Exp Clin Cancer Res. 2010 May 19;29:51
pubmed: 20482858
Nucleic Acids Res. 2003 Feb 15;31(4):e15
pubmed: 12582260
CA Cancer J Clin. 2018 Jan;68(1):7-30
pubmed: 29313949
Biochim Biophys Acta. 2007 May;1773(5):642-52
pubmed: 16926057
Cancer Lett. 2015 May 1;360(2):171-6
pubmed: 25684665
Clin Cancer Res. 2011 Jan 1;17(1):12-8
pubmed: 20966355
Oncol Rep. 2016 May;35(5):2743-54
pubmed: 26936386
Neoplasia. 2006 Apr;8(4):279-89
pubmed: 16756720
J Hematol Oncol. 2018 May 10;11(1):64
pubmed: 29747682
Br J Surg. 2000 Aug;87(8):992-1005
pubmed: 10931041
Biomed Res Int. 2013;2013:421821
pubmed: 24199193
Br J Cancer. 2014 Aug 26;111(5):817-22
pubmed: 24755884
Clin Cancer Res. 2004 May 15;10(10):3448-56
pubmed: 15161701
Phys Biol. 2012 Oct;9(5):055001
pubmed: 23011283
Curr Biol. 2002 Jan 8;12(1):79-84
pubmed: 11790308
Int J Biol Sci. 2016 Jan 28;12(3):338-46
pubmed: 26929740
Annu Rev Biophys Biomol Struct. 2007;36:451-77
pubmed: 17477841
Cancer Res. 2005 Apr 1;65(7):2532-6
pubmed: 15805244
Nat Rev Dis Primers. 2016 Apr 21;2:16022
pubmed: 27158978
J Biol Chem. 1999 Apr 23;274(17):11549-56
pubmed: 10206961
PLoS One. 2018 Mar 29;13(3):e0195126
pubmed: 29596489
Cancer Res. 2016 Apr 15;76(8):2419-31
pubmed: 26880805
Biochem Soc Trans. 2017 Feb 8;45(1):79-88
pubmed: 28202661
Oncol Rep. 2011 Dec;26(6):1595-9
pubmed: 21894436
Cancer Metastasis Rev. 2009 Jun;28(1-2):65-76
pubmed: 19160018
Genes Cancer. 2011 Mar;2(3):261-74
pubmed: 21779497
Aging (Albany NY). 2015 Sep;7(9):609-10
pubmed: 26420819
Mol Cell. 2002 Mar;9(3):459-70
pubmed: 11931755
Cancer Metastasis Rev. 2009 Jun;28(1-2):51-63
pubmed: 19165420
Anticancer Res. 2013 Jan;33(1):45-52
pubmed: 23267127
Cell Logist. 2012 Apr 1;2(2):105-116
pubmed: 23162742
J Cell Physiol. 2010 Aug;224(2):559-65
pubmed: 20432459
EMBO J. 1999 Oct 1;18(19):5310-20
pubmed: 10508164
Mol Biol Cell. 2006 Apr;17(4):1888-96
pubmed: 16467374
Nat Rev Cancer. 2014 Jan;14(1):13-25
pubmed: 24505617
Cell. 1995 May 5;81(3):323-30
pubmed: 7736585
J Cell Sci. 2011 Mar 1;124(Pt 5):679-83
pubmed: 21321325
Ann Surg Oncol. 2007 Dec;14(12):3629-37
pubmed: 17909916
Cancer Res. 2001 Jul 1;61(13):5275-83
pubmed: 11431370
PLoS One. 2014 Sep 03;9(9):e106343
pubmed: 25184537
Mol Med Rep. 2016 May;13(5):4414-20
pubmed: 27052944
Toxicol Sci. 2012 Oct;129(2):363-71
pubmed: 22696236
FEBS Lett. 2008 Jun 18;582(14):2102-11
pubmed: 18396168
J Cell Sci. 2017 Mar 15;130(6):1078-1093
pubmed: 28167680
J Biol Chem. 1999 May 28;274(22):15538-46
pubmed: 10336448
Wiley Interdiscip Rev Syst Biol Med. 2014 Sep-Oct;6(5):353-69
pubmed: 25269159
PLoS One. 2011;6(11):e27309
pubmed: 22087286
Front Physiol. 2020 Jul 31;11:848
pubmed: 32848827
Biochem Biophys Res Commun. 2011 Aug 26;412(2):279-85
pubmed: 21820414
BMC Bioinformatics. 2011 Mar 17;12:77
pubmed: 21414208
Pancreatology. 2002;2(2):129-37
pubmed: 12123093
J Cell Biol. 2013 Aug 19;202(4):653-66
pubmed: 23940119
Colomb Med (Cali). 2012 Sep 30;43(3):235-43
pubmed: 24893199
J Cell Sci. 2004 Jul 15;117(Pt 16):3499-510
pubmed: 15252126
Mol Cell Biol. 2008 Oct;28(20):6462-72
pubmed: 18710949
Cancers (Basel). 2020 Dec 02;12(12):
pubmed: 33276543
Nat Cell Biol. 2003 Dec;5(12):1083-9
pubmed: 14634665
PLoS Comput Biol. 2017 Dec 4;13(12):e1005741
pubmed: 29206223
PLoS One. 2012;7(10):e46798
pubmed: 23056457
Pancreatology. 2015 Jan-Feb;15(1):8-18
pubmed: 25547205
Evid Based Complement Alternat Med. 2016;2016:8203789
pubmed: 27872653
Oncol Lett. 2013 Mar;5(3):756-760
pubmed: 23426872
Biochem Soc Trans. 2012 Oct;40(5):981-8
pubmed: 22988851
Biophys J. 2013 Nov 5;105(9):1946-55
pubmed: 24209839
Oncotarget. 2017 Mar 21;8(12):20380-20393
pubmed: 28099910
Int J Mol Sci. 2016 Dec 22;18(1):
pubmed: 28025492
Curr Genomics. 2009 Nov;10(7):511-25
pubmed: 20436877
PLoS One. 2013;8(1):e54020
pubmed: 23326564
Cancer Res. 2003 Aug 15;63(16):4945-51
pubmed: 12941819
Oncotarget. 2017 Aug 3;8(39):66215-66225
pubmed: 29029505
Cancer Lett. 2013 Jun 28;334(1):109-17
pubmed: 23022268
Tumour Biol. 2014 Mar;35(3):2451-9
pubmed: 24197982
Cell Cycle. 2009 Nov 1;8(21):3455-61
pubmed: 19829074
Biochem Pharmacol. 2010 Dec 15;80(12):1946-54
pubmed: 20621068
Ann Oncol. 2012 Oct;23 Suppl 7:vii33-40
pubmed: 22997452
Cell Signal. 2013 Feb;25(2):457-69
pubmed: 23153585
Int J Cancer. 1975 May 15;15(5):741-7
pubmed: 1140870
Lab Invest. 1995 Apr;72(4):395-404
pubmed: 7723277
Int J Cancer. 2005 May 1;114(5):675-82
pubmed: 15609303
F1000 Biol Rep. 2010 Aug 19;2:62
pubmed: 21173851
Cancers (Basel). 2014 Apr 16;6(2):926-57
pubmed: 24743778
Cancer Res. 2010 Nov 15;70(22):9118-28
pubmed: 21045147
Bioinformatics. 2010 May 15;26(10):1378-80
pubmed: 20378558
Cancer Sci. 2006 Aug;97(8):697-702
pubmed: 16800820
Nature. 2018 Feb 1;554(7690):62-68
pubmed: 29364867
CA Cancer J Clin. 2018 Nov;68(6):394-424
pubmed: 30207593
Mol Cancer. 2008 Jul 24;7:64
pubmed: 18652674
PLoS One. 2015 Apr 07;10(4):e0122946
pubmed: 25849100
Int J Cancer. 2007 Apr 15;120(8):1634-40
pubmed: 17236203
Oncol Lett. 2016 Oct;12(4):2880-2885
pubmed: 27698874
Hum Pathol. 2011 Apr;42(4):516-21
pubmed: 21237490
Cancer Lett. 2009 Jan 18;273(2):194-200
pubmed: 18606491
Comput Struct Biotechnol J. 2020 Mar 10;18:571-582
pubmed: 32257043
Mol Cancer Res. 2017 Dec;15(12):1764-1776
pubmed: 28851812
Int J Clin Exp Pathol. 2015 Jun 01;8(6):6724-31
pubmed: 26261555
Clin Cancer Res. 2016 Nov 15;22(22):5592-5604
pubmed: 27267855
Oncotarget. 2017 Jun 13;8(24):39131-39142
pubmed: 28388575
Oncogene. 2005 Oct 6;24(44):6626-36
pubmed: 16103885
Clin Cancer Res. 2017 Mar 15;23(6):1607-1620
pubmed: 27637888
J Theor Biol. 1969 Mar;22(3):437-67
pubmed: 5803332
PLoS One. 2014 May 19;9(5):e98090
pubmed: 24840177
World J Gastroenterol. 2016 Nov 28;22(44):9694-9705
pubmed: 27956793
Nat Rev Cancer. 2007 Jun;7(6):429-40
pubmed: 17522712
JAKSTAT. 2014 Jun 12;3:e29554
pubmed: 25105067
Comput Methods Programs Biomed. 2011 Nov;104(2):227-34
pubmed: 21705106
J Hematol Oncol. 2017 Jan 6;10(1):9
pubmed: 28061880