An integrative analysis of chemically-induced cirrhosis-associated hepatocarcinogenesis: Histological, biochemical and molecular features

Author(s)

Romualdo, Guilherme Ribeiro ^[1] ; Grassi, Tony Fernando ^[2] ; Goto, Renata Leme ^[2] ; Tablas, Mariana Baptista ^[2] ; Bidinotto, Lucas Tadeu ^{[3, 4]} ; Henrique Fernandes, Ana Angelica ^[5] ; Cogliati, Bruno ^[6] ; Barbisan, Luis Fernando ^[2]

Affiliation

^[1] Sao Paulo State Univ UNESP, Botucatu Med Sch, Dept Pathol, Botucatu, SP - Brazil

^[2] Sao Paulo State Univ UNESP, Inst Biosci, Dept Morphol, Botucatu, SP - Brazil

^[3] Barretos Canc Hosp, Mol Oncol Res Ctr, Barretos, SP - Brazil

^[4] Dr Paulo Prata FACISB, Barretos Sch Hlth Sci, Barretos, SP - Brazil

^[5] Sao Paulo State Univ UNESP, Inst Biosci, Dept Chem & Biochem, Botucatu, SP - Brazil

^[6] Sao Paulo Univ USP, Sch Vet Med & Anim Sci, Dept Pathol, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Toxicology Letters; v. 281, p. 84-94, NOV 5 2017.
• Web of Science Citations: 5

Abstract

This study aimed the integrative characterization of morphological, biochemical and molecular features of chemically-induced cirrhosis-associated hepatocarcinogenesis. Thus, male Wistar rats were submitted to a diethylnitrosamine (DEN)/thioacetamide (TAA)-induced model. Liver tissue was processed for global gene expression, histopathological and collagen evaluations; as well as immunohistochemical and oxidative stress analysis. Gene Ontology and functional analysis showed the upregulation of extracellular matrix deposition genes, such as collagen type I alpha 1 and 2 (Col1 alpha 1 and Col1 alpha 2) and tissue inhibitor of metalloproteinase 1 and 2 genes (Timp1 and Timp2). In agreement these findings, animals presented extensive liver cirrhosis with increased collagen deposition (Sirius red). Besides, the animals developed many glutathione S-transferase pi (GST-P)-positive preneoplastic lesions showing high cell proliferation (Ki-67), in keeping with the Gstp1 and Gstp2 increased gene expression. DEN/TAA-treated rats also showed the upregulation of tumorigenesis-related annexin A2 gene (Anxa2) and few neoplastic lesions (hepatocellular adenomas, carcinomas, and cholangiocarcinoma). In contrast, gene expression and activity of antioxidant enzymes were decreased (glutathione peroxidase, total glutathione-S-transferase, and catalase). The model featured remarkable similarities to human hepatocarcinogenesis. Our findings could bring up new molecular insights into cirrhosis-associated hepatocarcinogenesis, and provide a suitable animal model for the establishment of further diagnostic, preventive and therapeutic approaches. (AU)

• FAPESP's process: 10/14110-4 - In Utero endocrine-disrupting bisphenol A exposure and chemopreventive agents on susceptibility to mammary carcinogenesis in female Sprague-Dawley.
• Grantee: Luís Fernando Barbisan
• Support Opportunities: Regular Research Grants