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MyD88-dependent signaling in non-parenchymal cells promotes liver carcinogenesis
- Source :
- CARCINOGENESIS, 41(2), 171-181. Oxford University Press, Carcinogenesis, 171. Oxford University Press, STARTPAGE=171;ISSN=0143-3334;TITLE=Carcinogenesis
- Publication Year :
- 2020
- Publisher :
- Oxford University Press, 2020.
-
Abstract
- In Western countries, a rising incidence of obesity and type 2 diabetes correlates with an increase of non-alcoholic steatohepatitis (NASH)—a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). NASH is associated with chronic liver injury, triggering hepatocyte death and enhanced translocation of intestinal bacteria, leading to persistent liver inflammation through activation of Toll-like receptors and their adapter protein myeloid differentiation factor 88 (MyD88). Therefore, we investigated the role of MyD88 during progression from NASH to HCC using a mouse model of chronic liver injury (hepatocyte-specific deletion of nuclear factor κB essential modulator, Nemo; NemoΔhepa). NemoΔhepa; NemoΔhepa/MyD88−/− and NemoΔhepa/MyD88Δhepa were generated and the impact on liver disease progression was investigated. Ubiquitous MyD88 ablation (NemoΔhepa/MyD88−/−) aggravated the degree of liver damage, accompanied by an overall decrease in inflammation, whereas infiltrating macrophages and natural killer cells were elevated. At a later stage, MyD88 deficiency impaired HCC formation. In contrast, hepatocyte-specific MyD88 deletion (NemoΔhepa/MyD88Δhepa) did not affect disease progression. These results suggest that signaling of Toll-like receptors through MyD88 in non-parenchymal liver cells is required for carcinogenesis during chronic liver injury. Hence, blocking MyD88 signaling may offer a therapeutic option to prevent HCC formation in patients with NASH.
- Subjects :
- 0301 basic medicine
Male
Cancer Research
Cirrhosis
Liver cytology
Carcinogenesis
NF-KAPPA-B
STEATOHEPATITIS
ACTIVATION
Liver disease
Mice
0302 clinical medicine
Non-alcoholic Fatty Liver Disease
Mice, Knockout
Liver Neoplasms
Intracellular Signaling Peptides and Proteins
hemic and immune systems
General Medicine
CANCER
medicine.anatomical_structure
Liver
030220 oncology & carcinogenesis
Hepatocyte
Hepatocellular carcinoma
Disease Progression
medicine.symptom
Signal Transduction
EXPRESSION
congenital, hereditary, and neonatal diseases and abnormalities
Carcinoma, Hepatocellular
NEMO/IKK-GAMMA
Inflammation
IMMUNITY
03 medical and health sciences
INFLAMMATION
medicine
TUMORIGENESIS
Animals
Humans
TOLL-LIKE RECEPTORS
business.industry
medicine.disease
digestive system diseases
Disease Models, Animal
030104 developmental biology
Myeloid Differentiation Factor 88
Cancer research
Hepatocytes
Steatohepatitis
business
Subjects
Details
- Language :
- English
- ISSN :
- 01433334
- Volume :
- 41
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- CARCINOGENESIS
- Accession number :
- edsair.doi.dedup.....472bf40fb8910d4ae015b3eb96cb55f5