An integrative analysis of chemically-induced cirrhosis-associated hepatocarcinogenesis: Histological, biochemical and molecular features. (5th November 2017)

• Record Type: Journal Article
• Authors: Romualdo, Guilherme Ribeiro; Grassi, Tony Fernando; Goto, Renata Leme; Tablas, Mariana Baptista; Bidinotto, Lucas Tadeu; Fernandes, Ana Angélica Henrique; Cogliati, Bruno; Barbisan, Luís Fernando
• Is Part Of: Toxicology letters. Volume 281(2017)
• Page Start: 84
• Page End: 94
• Publication Date: 2017-11-05
• Subjects: Hepatocarcinogenesis -- Liver cirrhosis -- Diethylnitrosamine -- Thioacetamide -- Oligo microarray -- Wistar rats; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2017.09.015
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: We proposed an integrative cirrhosis-associated hepatocarcinogenesis model. Animals developed many hyperplastic glutathione-S-transferase pi positive nodules. Extracellular matrix genes were upregulated ( Col1α1, Col1α2, Timp1, Timp2 ). Antioxidant enzymes genes and activity were decreased ( Gpx1, Gstm3, Cat ). Findings bring up new molecular insights and provide a suitable animal model. 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 ( Col1α1 and Col1α2) 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.