PUBLICATION
microRNA-21 promotes dysregulated lipid metabolism and hepatocellular carcinoma
- Authors
- VanSant-Webb, C., Castro, J.C., Su, A.Y., Hawkins, K., Saxena, A., Wright, J., Smith, R., García, M.F., Chen, Y.A., Barton, C., Stubben, C., O'Connell, R.M., Ducker, G.S., Evason, K.J.
- ID
- ZDB-PUB-260126-6
- Date
- 2026
- Source
- Disease models & mechanisms : (Journal)
- Registered Authors
- Castro, Jessye, Evason, Kimberley, Saxena, Aavrati, Smith, Richard, VanSant-Webb, Chad
- Keywords
- Acylcarnitines, Liver, Steatosis, Zebrafish, β-catenin
- Datasets
- GEO:GSE320275
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Carcinoma, Hepatocellular*/genetics
- Carcinoma, Hepatocellular*/metabolism
- Carcinoma, Hepatocellular*/pathology
- Gene Expression Regulation, Neoplastic
- Hepatocytes/metabolism
- Hepatocytes/pathology
- Humans
- Larva/metabolism
- Lipid Metabolism*/genetics
- Liver/metabolism
- Liver/pathology
- Liver Neoplasms*/genetics
- Liver Neoplasms*/metabolism
- Liver Neoplasms*/pathology
- MicroRNAs*/genetics
- MicroRNAs*/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- beta Catenin/metabolism
- PubMed
- 41582686 Full text @ Dis. Model. Mech.
Citation
VanSant-Webb, C., Castro, J.C., Su, A.Y., Hawkins, K., Saxena, A., Wright, J., Smith, R., García, M.F., Chen, Y.A., Barton, C., Stubben, C., O'Connell, R.M., Ducker, G.S., Evason, K.J. (2026) microRNA-21 promotes dysregulated lipid metabolism and hepatocellular carcinoma. Disease models & mechanisms. :.
Abstract
The prevalence of hepatocellular carcinoma (HCC) is rising in parallel with increasing obesity and metabolic dysfunction-associated steatohepatitis (MASH). MicroRNAs are key post-transcriptional regulators of gene expression and are attractive targets for HCC therapy. Here we sought to identify and characterize dysregulated microRNAs in MASH-driven HCC (MASH-HCC). We profiled microRNA expression in liver tissue from patients with MASH or MASH-HCC and in zebrafish HCC driven by activated β-catenin (ABC), one of the most commonly mutated oncogenes in MASH-HCC. We found overlap between dysregulated human and zebrafish miRNAs, including miR-21, which was increasingly upregulated from normal liver to MASH to MASH-HCC. We generated transgenic zebrafish that overexpress or sponge miR-21 in hepatocytes. We found that miR-21 overexpression caused larval liver overgrowth and increased HCC, while miR-21 sponge suppressed β-catenin-driven larval liver overgrowth. By performing histologic and lipidomic analysis, we found that overexpression of miR-21, like ABC, suppressed lipid accumulation in response to a high cholesterol diet and increased accumulation of acylcarnitines. Thus miR-21, which is similarly upregulated in human and zebrafish HCC, promotes lipid metabolic changes that may help drive hepatocarcinogenesis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping