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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Fibrosis-associated hepatocarcinogenesis revisited: Establishing standard medium-term chemically-induced male and female models

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Romualdo, Guilherme Ribeiro [1] ; Prata, Gabriel Bacil [2] ; da Silva, Tereza Cristina [3] ; Henrique Fernandes, Ana Angelica [4] ; Moreno, Fernando Salvador [5] ; Cogliati, Bruno [3] ; Barbisan, Luis Fernando [2]
Total Authors: 7
[1] Sao Paulo State Univ UNESP, Botucatu Med Sch, Dept Pathol, Botucatu, SP - Brazil
[2] Sao Paulo State Univ UNESP, Biosci Inst, Dept Morphol, Botucatu, SP - Brazil
[3] Univ Sao Paulo, Sch Vet Med & Anim Sci, Dept Pathol, Sao Paulo, SP - Brazil
[4] Sao Paulo State Univ UNESP, Biosci Inst, Dept Chem & Biochem, Botucatu, SP - Brazil
[5] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Food & Expt Nutr, Sao Paulo, SP - Brazil
Total Affiliations: 5
Document type: Journal article
Source: PLoS One; v. 13, n. 9 SEP 13 2018.
Web of Science Citations: 1

Hepatocellular carcinoma causes similar to 10% of all cancer-related deaths worldwide, usually emerging in a background of liver fibrosis/cirrhosis (70%-90% of cases). Chemically-induced mouse models for fibrosis-associated hepatocarcinogenesis are widely-applied, resembling the corresponding human disease. Nonetheless, a long time is necessary for the development of preneoplastic/neoplastic lesions. Thus, we proposed an early fibrosis-associated hepatocarcinogenesis model for male and female mice separately, focusing on reducing the experimental time for preneoplastic/neoplastic lesions development and establishing standard models for both sexes. Then, two-week old susceptible C3H/HeJ male and female mice (n = 8 animals/sex/group) received a single dose of diethylnitrosamine (DEN, 10 or 50 mg/Kg). During 2 months, mice received 3 weekly doses of carbon tetrachloride (CCl4, 10% corn oil solution, 0.25 to 1.50 mu L/g b.wt.) and they were euthanized at week 17. DEN/CCl4 protocols for males and females displayed clear liver fibrosis, featuring collagen accumulation and hepatic stellate cell activation (alpha-SMA). In addition, liver from males displayed increased CD68+ macrophage number, COX-2 protein expression and IL-6 levels. The DEN/CCl4 models in both sexes impaired antioxidant defense as well as enhanced hepatocyte proliferation and apoptosis. Moreover, DEN/CCl4-treated male and female developed multiple preneoplastic altered hepatocyte foci and hepatocellular adenomas. As expected, the models showed clear male bias. Therefore, we established standard and suitable fibrosis-associated hepatocarcinogenesis models for male and female mice, shortening the experimental time for the development of hepatocellular preneoplastic/neoplastic lesions in comparison to other classical models. (AU)

FAPESP's process: 16/14420-0 - MiRNA expression in fibrosis-associated hepatocarcinogenesis: modulation by caffeine, trigonelline and chlorogenic acid
Grantee:Luís Fernando Barbisan
Support type: Regular Research Grants