INHIBITION OF DAPK3, PINPOINTED AS A KEY FACTOR IN THE DEVELOPMENT OF COLITIS-ASSOCIATED DYSPLASIA, INCREASES SEVERITY OF DSS-INDUCED COLITIS VIA HIPPO SIGNALING
Notice bibliographique
Résumé
Abstract Introduction Ulcerative colitis (UC) is a progressive disorder that elevates the risk of cancer development through a colitis-dysplasia-carcinoma sequence. Recent evidence demonstrates the necessity of Hippo-YAP/TAZ signaling, interceded by cytoskeletal remodeling, for intestinal regeneration. Death-associated protein kinase 3 (DAPK3) is a regulator of actin-cytoskeleton reorganization that controls proliferation and apoptosis. We first identified DAPK3 as a candidate gene involved in UC progression, and then examined if inhibition of DAPK3 would increase the severity of colitis. Methods Data series GSE47908 [1] comprising microarray expression profile of biopsies from left colon of healthy controls and UC patients with left-sided colitis, pancolitis, or UC-associated dysplasia was retrieved from Gene Expression Omnibus. Differentially expressed genes (DEGs) were analyzed using Ingenuity Pathway Analysis software and topGO R. C57BL/6 mice receiving 2.5% (wt./vol.) DSS or water (7 days) were treated daily s.c. with the DAPK3 pharmacological inhibitor HS38 [2] or vehicle for 12 days (pretreatment: 3 days, recovery: 2 days). Colitis was assessed by disease activity index and histopathology. Intestinal epithelial cell (IEC) proliferation was enumerated via Ki-67 immunohistochemistry (IHC). DAPK3 and YAP abundances were evaluated by immunoblot, and YAP subcellular localization was assessed by IHC. Results topGO analysis showed enrichment of inflammatory processes in pancolitis Π left-side colitis DEGs and enrichment of actin-based processes in pancolitis Π dysplasia DEGs. Pathway analysis revealed trend of Hippo signaling activation as UC progressed from left-side to pancolitis to UC-associated dysplasia. Network analysis implicated DAPK3 as a key factor in colitis-dysplasia progression. Mice treated with DSS showed decreased colonic DAPK3 abundance. Mice co-treated with DSS/HS38 showed significantly increased histological score, and decreased IEC proliferation in comparison with DSS/vehicle controls. Moreover, H2O/HS38 treated mice showed increased colonic YAP abundance versus H2O/vehicle controls while DSS/HS38 co-treatment elicited nuclear accumulation of YAP in IECs localized at the crypt apex. Conclusion DAPK3 is a key factor in intestinal regeneration and UC progression by way of Hippo-YAP signaling. This is potentially arbitrated by DAPK3-dependent reorganization of actin cytoskeleton and focal adhesion dynamics. References: 1. Bjerrum, Jacob T et al. “Transcriptional analysis of left-sided colitis, pancolitis, and ulcerative colitis-associated dysplasia.” Inflamm Bowel Dis vol. 20,12 (2014): 2340–52. [2] Carlson, David A et al. “Fluorescence linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor.” ACS Chem Biol vol. 8,12 (2013): 2715–23. Funding Agencies Canadian Institutes of Health Research. Identification of DAPK3 as a potential key factor in UC progression. (A) Networks were constructed for each colitis subtypes based on known molecular interactions of DEGs: Black octagons are networks constructed with dysplasia DEGs, grey hexagons are pancolitis networks, and white rectangles are left-side colitis networks. Shape size represents the relative number of DEGs used to build said network. The networks are connected to one another if there are any overlapping molecules. Line width represent the number of shared molecules. By focusing on networks that had >85% of DEG inputs and keeping edges that involved >5% overlap of common molecules, we arrived at the core network of networks (B) that was heavily leveraged on the edge connecting dysplasia network 1 and pancolitis network 15 (C). One kinase (DAPK3) was identified at this intersection, whose inhibition was test in an animal model of colitis (D).
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».