Aberrant glycosaminoglycan biosynthesis by tumor suppressor EXTL2 deficiency promotes liver inflammation and tumorigenesis through Toll-like 4 receptor signaling.
Animals
Carcinogenesis
/ metabolism
Carcinoma, Hepatocellular
/ metabolism
Cell Line
Cell Transformation, Neoplastic
/ metabolism
Glycosaminoglycans
/ biosynthesis
Hepatitis
/ metabolism
Inflammation
/ metabolism
Liver
/ metabolism
Liver Neoplasms
/ metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
N-Acetylglucosaminyltransferases
/ deficiency
NF-kappa B
/ metabolism
Non-alcoholic Fatty Liver Disease
Proteoglycans
/ metabolism
RAW 264.7 Cells
Signal Transduction
/ physiology
Toll-Like Receptor 4
/ metabolism
NF-kappaB (NF-κB)
glycosaminoglycan
inflammation
liver cancer
proteoglycans (PG)
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
13
08
2019
revised:
30
03
2020
accepted:
11
04
2020
pubmed:
30
4
2020
medline:
16
1
2021
entrez:
30
4
2020
Statut:
ppublish
Résumé
Certain proteoglycans, consisting of a core protein and glycosaminoglycan (GAG) chains, are among the many types of biomolecules that can function as damage-associated molecular pattern molecules (DAMPs). We, therefore, hypothesized that the expression level and structural alteration of GAGs affect inflammation. We have previously reported that the effects on GAG biosynthesis caused by loss of the tumor suppressor gene exostosin-like 2 (Extl2) influence liver injury and regeneration processes. To examine how altered GAG biosynthesis may underscore the relationship between inflammation and tumorigenesis, we assessed its role in non-alcoholic steatohepatitis and hepatocarcinoma (HCC) induced by dietary obesity and insulin-resistance. We demonstrated that GAGs produced in the absence of EXTL2 act as DAMPs and directly input signals into cells via the Toll-like 4 receptor. In addition, the subsequent transcriptional activation of inflammatory and tumor-promoting cytokines by NF-κB contributes to injury- and inflammation-driven tumor promotion. Thus, dysregulated biosynthesis of GAGs is considered to increase the risk of HCC in a background of obesity and diabetes.
Identifiants
pubmed: 32347583
doi: 10.1096/fj.201902076R
doi:
Substances chimiques
Glycosaminoglycans
0
NF-kappa B
0
Proteoglycans
0
Tlr4 protein, mouse
0
Toll-Like Receptor 4
0
EXTL2 protein, mouse
EC 2.4.1.-
N-Acetylglucosaminyltransferases
EC 2.4.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8385-8401Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
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