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

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 13, n. 9 SEP 13 2018.
• Citações Web of Science: 1

Resumo

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)

• Processo FAPESP: 16/14420-0 - Expressão de miRNAs na hepatocarcinogênese associada à fibrose: modulação pela cafeína, trigonelina e ácido clorogênico
• Beneficiário: Luís Fernando Barbisan
• Linha de fomento: Auxílio à Pesquisa - Regular