A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.
Animals
Carcinogenesis
/ pathology
Carcinoma, Hepatocellular
/ pathology
Cell Line, Tumor
Chemoprevention
Cohort Studies
Cyclic AMP
/ metabolism
Cyclic AMP Response Element-Binding Protein
/ metabolism
Disease Models, Animal
Drug Discovery
Gene Expression Regulation, Neoplastic
/ drug effects
HEK293 Cells
Hepacivirus
/ physiology
Hepatitis C
/ genetics
Hepatocytes
/ drug effects
Humans
Immunologic Surveillance
/ drug effects
Inflammation
/ pathology
Liver
/ drug effects
Liver Cirrhosis
/ pathology
Liver Neoplasms
/ pathology
Macrophages
/ drug effects
Male
Mice, Knockout
Models, Biological
Nizatidine
/ pharmacology
Prognosis
Signal Transduction
/ drug effects
Transcriptome
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 09 2021
17 09 2021
Historique:
received:
16
07
2020
accepted:
03
08
2021
entrez:
18
9
2021
pubmed:
19
9
2021
medline:
13
10
2021
Statut:
epublish
Résumé
Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2
Identifiants
pubmed: 34535664
doi: 10.1038/s41467-021-25468-9
pii: 10.1038/s41467-021-25468-9
pmc: PMC8448834
doi:
Substances chimiques
Cyclic AMP Response Element-Binding Protein
0
Cyclic AMP
E0399OZS9N
Nizatidine
P41PML4GHR
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5525Subventions
Organisme : NCI NIH HHS
ID : K01 CA140861
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA209940
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099558
Pays : United States
Organisme : NIAID NIH HHS
ID : R03 AI131066
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA233794
Pays : United States
Informations de copyright
© 2021. The Author(s).
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