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Loss of Hepatic Transcription Factor EB Attenuates Alcohol-Associated Liver Carcinogenesis
- Source :
- Am J Pathol
- Publication Year :
- 2022
- Publisher :
- Elsevier BV, 2022.
-
Abstract
- Alcohol is a well-known risk factor for hepatocellular carcinoma. Autophagy plays a dual role in liver cancer, as it suppresses tumor initiation and promotes tumor progression. Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy, which is impaired in alcohol-related liver disease. However, the role of TFEB in alcohol-associated liver carcinogenesis is unknown. Liver-specific Tfeb knockout (KO) mice and their matched wild-type (WT) littermates were injected with the carcinogen diethylnitrosamine (DEN), followed by chronic ethanol feeding. We found that the numbers of both total and larger tumors increased significantly in DEN-treated mice fed with ethanol diet than in mice fed with control diet. Although the number of tumors was not different between WT and L-Tfeb KO mice fed either control or ethanol diet, the number of larger tumors was less in L-Tfeb KO mice than in WT mice. To our surprise, no differences were found in liver injury, steatosis, inflammation, ductular reaction, fibrosis, and tumor cell proliferation in DEN-treated mice fed ethanol. However, the levels of glypican 3, a marker of malignant hepatocellular carcinoma, markedly decreased in DEN-treated L-Tfeb KO mice fed ethanol in comparison to the WT mice. Our findings indicate that chronic ethanol feeding promotes DEN-initiated liver tumor development, which tends to be attenuated by genetic deletion of hepatic TFEB.
- Subjects :
- Liver Cirrhosis
Male
medicine.medical_specialty
Carcinoma, Hepatocellular
Liver tumor
Alcohol Drinking
Carcinogenesis
Tumor initiation
Biology
Models, Biological
Pathology and Forensic Medicine
Liver disease
Liver Neoplasms, Experimental
Internal medicine
medicine
Animals
Diethylnitrosamine
Cell Proliferation
Inflammation
Mice, Knockout
Liver injury
Ethanol
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Liver Neoplasms
Regular Article
medicine.disease
Tumor Burden
Mice, Inbred C57BL
Endocrinology
Liver
Diet, Western
Tumor progression
TFEB
Steatosis
Liver cancer
Gene Deletion
Subjects
Details
- ISSN :
- 00029440
- Volume :
- 192
- Database :
- OpenAIRE
- Journal :
- The American Journal of Pathology
- Accession number :
- edsair.doi.dedup.....870be4e1c85f0577cd1e834ac7695ed0