Author, as appears in the article.: Fekry B; Ribas-Latre A; Baumgartner C; Mohamed A; Kolonin M; Sladek F; Younes M; Eckel-Mahan K
Department: Medicina i Cirurgia
URV's Author/s: Ribas Latre, Aleix
Abstract: ©©2019 American Association for Cancer Research. The incidence of hepatocellular carcinoma (HCC) is on the rise worldwide. Although the incidence of HCC in males is considerably higher than in females, the projected rates of HCC incidence are increasing for both sexes. A recently appreciated risk factor for HCC is the growing problem of nonalcoholic fatty liver disease, which is usually associated with obesity and the metabolic syndrome. In this study, we showed that under conditions of fatty liver, female mice were more likely to develop HCC than expected from previous models. Using an inducible knockout model of the tumor-suppressive isoform of hepatocyte nuclear factor 4 alpha (P1-HNF4α) in the liver in combination with prolonged high fat (HF) diet, we found that HCC developed equally in male and female mice as early as 38 weeks of age. Similar sex-independent HCC occurred in the STAM model of mice, in which severe hyperglycemia and HF feeding results in rapid hepatic lipid deposition, fibrosis, and ultimately HCC. In both sexes, reduced P1-HNF4α activity, which also occurs under chronic HF diet feeding, increased hepatic lipid deposition and produced a greatly augmented circadian rhythm in IL6, a factor previously linked with higher HCC incidence in males. Loss of HNF4α combined with HF feeding induced epithelial–mesenchymal transition in an IL6-dependent manner. Collectively, these data provide a mechanism-based working hypothesis that could explain the rising incidence of aggressive HCC. Significance: This study provides a mechanism for the growing incidence of hepatocellular carcinoma in both men and women, which is linked to nonalcoholic fatty liver disease.
Thematic Areas: Astronomia / física Biotecnología Cancer research Ciências biológicas i Ciências biológicas ii Ciências biológicas iii Farmacia General medicine Interdisciplinar Medicina i Medicina ii Medicina iii Medicina veterinaria Odontología Oncology Química Saúde coletiva
licence for use: https://creativecommons.org/licenses/by/3.0/es/
Author's mail: aleix.ribas@urv.cat
Record's date: 2023-02-19
Papper version: info:eu-repo/semantics/acceptedVersion
Link to the original source: https://aacrjournals.org/cancerres/article/79/22/5860/638347/HNF4-Deficient-Fatty-Liver-Provides-a-Permissive
Papper original source: Cancer Research. 79 (22): 5860-5873
APA: Fekry B; Ribas-Latre A; Baumgartner C; Mohamed A; Kolonin M; Sladek F; Younes M; Eckel-Mahan K (2019). HNF4a-deficient fatty liver provides a permissive environment for sex-independent hepatocellular carcinoma. Cancer Research, 79(22), 5860-5873. DOI: 10.1158/0008-5472.CAN-19-1277
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Article's DOI: 10.1158/0008-5472.CAN-19-1277
Entity: Universitat Rovira i Virgili
Journal publication year: 2019
Publication Type: Journal Publications