Faculty, Staff and Student Publications
Publication Date
1-30-2024
Journal
Cell Communication and Signaling
Abstract
Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver diseases and has emerged as the leading factor in the pathogenesis of hepatocellular carcinoma (HCC). MyD88 contributes to the development of HCC. However, the underlying mechanism by which MyD88 in myofibroblasts regulates NAFLD-associated liver cancer development remains unknown.
Results: Myofibroblast MyD88-deficient (SMAMyD88-/-) mice were protected from diet-induced obesity and developed fewer and smaller liver tumors. MyD88 deficiency in myofibroblasts attenuated macrophage M2 polarization and fat accumulation in HCC tissues. Mechanistically, MyD88 signaling in myofibroblasts enhanced CCL9 secretion, thereby promoting macrophage M2 polarization. This process may depend on the CCR1 receptor and STAT6/ PPARβ pathway. Furthermore, liver tumor growth was attenuated in mice treated with a CCR1 inhibitor. CCLl5 (homologous protein CCL9 in humans) expression was increased in myofibroblasts of HCC and was associated with shorter survival of patients with HCC. Thus, our results indicate that MyD88 in myofibroblasts promotes NAFLD-related HCC progression and may be a promising therapeutic target for HCC treatment.
Conclusion: This study demonstrates that MyD88 in myofibroblasts can promote nonalcoholic fatty liver disease-related hepatocarcinogenesis by enhancing macrophage M2 polarization, which might provide a potential molecular therapeutic target for HCC.
Keywords
Animals, Humans, Mice, Carcinogenesis, Carcinoma, Hepatocellular, Liver Neoplasms, Macrophages, Myeloid Differentiation Factor 88, Myofibroblasts, Non-alcoholic Fatty Liver Disease, CCL9/CCL15, Hepatocellular carcinoma, Macrophage polarization, MyD88, Nonalcoholic fatty liver disease
DOI
10.1186/s12964-024-01489-x
PMID
38291436
PMCID
PMC10826060
PubMedCentral® Posted Date
1-30-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
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