Molecular Network Analyses Implicate Death-Associated Protein Kinase 3 (DAPK3) as a Key Factor in Colitis-Associated Dysplasia Progression.
colon cancer
death-associated protein kinase
differential-gene expression
dysplasia
ulcerative colitis
zipper-interacting protein kinase
Journal
Inflammatory bowel diseases
ISSN: 1536-4844
Titre abrégé: Inflamm Bowel Dis
Pays: England
ID NLM: 9508162
Informations de publication
Date de publication:
03 10 2022
03 10 2022
Historique:
received:
31
10
2021
pubmed:
24
5
2022
medline:
5
10
2022
entrez:
23
5
2022
Statut:
ppublish
Résumé
Ulcerative colitis (UC) is a progressive disorder that elevates the risk of colon cancer development through a colitis-dysplasia-carcinoma sequence. Gene expression profiling of colitis-associated lesions obtained from patients with varied extents of UC can be mined to define molecular panels associated with colon cancer development. Differential gene expression profiles of 3 UC clinical subtypes and healthy controls were developed for the GSE47908 microarray data set of healthy controls, left-sided colitis, pancolitis, and colitis-associated dysplasia (CAD) using limma R. A gene ontology enrichment analysis of differentially expressed genes (DEGs) revealed a shift in the transcriptome landscape as UC progressed from left-sided colitis to pancolitis to CAD, from being immune-centric to being cytoskeleton-dependent. Hippo signaling (via Yes-associated protein [YAP]) and Ephrin receptor signaling were the top canonical pathways progressively altered in concert with the pathogenic progression of UC. A molecular interaction network analysis of DEGs in left-sided colitis, pancolitis, and CAD revealed 1 pairwise line, or edge, that was topologically important to the network structure. This edge was found to be highly enriched in actin-based processes, and death-associated protein kinase 3 (DAPK3) was a critical member and sole protein kinase member of this network. Death-associated protein kinase 3 is a regulator of actin-cytoskeleton reorganization that controls proliferation and apoptosis. Differential correlation analyses revealed a negative correlation for DAPK3-YAP in healthy controls that flipped to positive in left-sided colitis. With UC progression to CAD, the DAPK3-YAP correlation grew progressively more positive. In summary, DAPK3 was identified as a candidate gene involved in UC progression to dysplasia. Our investigation verified pancolitis as a conduit for ulcerative colitis advancement from left-sided colitis to dysplasia and uniquely identified dysregulation of actin reorganization, with death-associated protein kinase 3 and Yes-associated protein as key molecular determinants for disease progression.
Sections du résumé
BACKGROUND
Ulcerative colitis (UC) is a progressive disorder that elevates the risk of colon cancer development through a colitis-dysplasia-carcinoma sequence. Gene expression profiling of colitis-associated lesions obtained from patients with varied extents of UC can be mined to define molecular panels associated with colon cancer development.
METHODS
Differential gene expression profiles of 3 UC clinical subtypes and healthy controls were developed for the GSE47908 microarray data set of healthy controls, left-sided colitis, pancolitis, and colitis-associated dysplasia (CAD) using limma R.
RESULTS
A gene ontology enrichment analysis of differentially expressed genes (DEGs) revealed a shift in the transcriptome landscape as UC progressed from left-sided colitis to pancolitis to CAD, from being immune-centric to being cytoskeleton-dependent. Hippo signaling (via Yes-associated protein [YAP]) and Ephrin receptor signaling were the top canonical pathways progressively altered in concert with the pathogenic progression of UC. A molecular interaction network analysis of DEGs in left-sided colitis, pancolitis, and CAD revealed 1 pairwise line, or edge, that was topologically important to the network structure. This edge was found to be highly enriched in actin-based processes, and death-associated protein kinase 3 (DAPK3) was a critical member and sole protein kinase member of this network. Death-associated protein kinase 3 is a regulator of actin-cytoskeleton reorganization that controls proliferation and apoptosis. Differential correlation analyses revealed a negative correlation for DAPK3-YAP in healthy controls that flipped to positive in left-sided colitis. With UC progression to CAD, the DAPK3-YAP correlation grew progressively more positive.
CONCLUSION
In summary, DAPK3 was identified as a candidate gene involved in UC progression to dysplasia.
Our investigation verified pancolitis as a conduit for ulcerative colitis advancement from left-sided colitis to dysplasia and uniquely identified dysregulation of actin reorganization, with death-associated protein kinase 3 and Yes-associated protein as key molecular determinants for disease progression.
Autres résumés
Type: plain-language-summary
(eng)
Our investigation verified pancolitis as a conduit for ulcerative colitis advancement from left-sided colitis to dysplasia and uniquely identified dysregulation of actin reorganization, with death-associated protein kinase 3 and Yes-associated protein as key molecular determinants for disease progression.
Identifiants
pubmed: 35604388
pii: 6590762
doi: 10.1093/ibd/izac098
pmc: PMC9527615
doi:
Substances chimiques
Actins
0
Ephrins
0
YAP-Signaling Proteins
0
DAPK3 protein, human
EC 2.7.11.1
Death-Associated Protein Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1485-1496Subventions
Organisme : CIHR
ID : MOP 97931
Pays : Canada
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Références
Nature. 2015 Mar 5;519(7541):57-62
pubmed: 25731159
Carcinogenesis. 2012 Jul;33(7):1375-83
pubmed: 22610167
F1000Res. 2020 Apr 24;9:
pubmed: 32399194
Gut. 2013 Jul;62(7):967-76
pubmed: 23135761
Biochem Soc Trans. 2021 Aug 27;49(4):1515-1527
pubmed: 34374419
United European Gastroenterol J. 2020 Jul;8(6):675-684
pubmed: 32268844
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Int J Exp Pathol. 2012 Oct;93(5):305-18
pubmed: 22974212
Aliment Pharmacol Ther. 2020 Jul;52(1):5-19
pubmed: 32432797
Genes Dev. 2010 Nov 1;24(21):2383-8
pubmed: 21041407
Lancet. 2012 Nov 3;380(9853):1606-19
pubmed: 22914296
Cell. 2011 Mar 4;144(5):782-95
pubmed: 21376238
World J Gastroenterol. 2015 Nov 7;21(41):11688-99
pubmed: 26556996
Gut. 2019 Jun;68(6):985-995
pubmed: 29991641
Science. 2012 Oct 5;338(6103):120-3
pubmed: 22903521
Inflamm Bowel Dis. 2014 Nov;20(11):2115-23
pubmed: 25337866
Nature. 2012 Nov 1;491(7422):119-24
pubmed: 23128233
Inflamm Bowel Dis. 2019 Jan 10;25(2):317-327
pubmed: 30452647
J Pediatr Gastroenterol Nutr. 2018 Jul;67(1):45-52
pubmed: 29401083
J Biol Chem. 2011 May 27;286(21):19170-7
pubmed: 21454679
Genes Dev. 2008 Feb 15;22(4):416-29
pubmed: 18281458
Eur J Pharmacol. 2019 Jun 5;852:90-98
pubmed: 30851272
Mol Biol Rep. 2020 Apr;47(4):3053-3063
pubmed: 32086718
J Proteome Res. 2011 Jan 7;10(1):200-9
pubmed: 20828217
Gastroenterology. 2016 Apr;150(4):808-10
pubmed: 26924087
Cancer Prev Res (Phila). 2016 Dec;9(12):887-894
pubmed: 27679553
Inflamm Bowel Dis. 2014 Oct;20(10):1802-12
pubmed: 25171508
Cell Stem Cell. 2018 Jan 4;22(1):35-49.e7
pubmed: 29249464
J Biol Chem. 2018 Mar 2;293(9):3073-3087
pubmed: 29317503
Phys Rev E Stat Nonlin Soft Matter Phys. 2004 Feb;69(2 Pt 2):026113
pubmed: 14995526
Cell Adh Migr. 2014;8(4):327-38
pubmed: 25482622
J Med Chem. 2009 Nov 26;52(22):7323-7
pubmed: 19877644
Inflamm Bowel Dis. 2013 Mar;19(3):461-70
pubmed: 23388545
Pathol Res Pract. 2010 Sep 15;206(9):616-24
pubmed: 20630662
Inflamm Bowel Dis. 2009 Apr;15(4):630-8
pubmed: 18942763
BMC Syst Biol. 2016 Nov 15;10(1):106
pubmed: 27846853
Cell Oncol. 2010 Jan 1;32(4):303-10
pubmed: 20208143
Clin Gastroenterol Hepatol. 2015 Feb;13(2):322-329.e1
pubmed: 25041865
Bioinformatics. 2006 Dec 15;22(24):3106-8
pubmed: 17060356
Gastroenterol Res Pract. 2019 Nov 03;2019:5363261
pubmed: 31781191
Genet Test Mol Biomarkers. 2010 Jun;14(3):347-53
pubmed: 20406101
Inflamm Bowel Dis. 2014 Dec;20(12):2340-52
pubmed: 25358065
Sci Transl Med. 2019 Mar 6;11(482):
pubmed: 30842312
PLoS One. 2017 Sep 21;12(9):e0184959
pubmed: 28934284
Sci Rep. 2020 Jul 28;10(1):12620
pubmed: 32724133
Sci Rep. 2016 Aug 30;6:32118
pubmed: 27573465
Gastroenterology. 2016 Apr;150(4):931-43
pubmed: 26764183
Front Pharmacol. 2019 Jun 17;10:691
pubmed: 31297055
J Pathol. 1998 Aug;185(4):413-8
pubmed: 9828841