title: Ductular reaction, cytokeratin 7 positivity, and gamma-glutamyl transferase in multistage hepatocarcinogenesis in rats.
abstract: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is characterized by multistage formation. The presence of ductular reaction, cytokeratin 7 positivity (PCK7), and increased levels of gamma glutamyltransferase (γGT) has been observed during liver carcinogenesis and contribute to tumor progression. Our goal was to evaluate the ductular reaction in multistage carcinogenesis and to correlate PCK7 and γGT levels with tumor incidence, histological characteristics, liver DNA damage index, and the expression of oxidative stress proteins. HCC was induced in 24 male Wistar rats weighing 145-150 g by chronic and intermittent exposure to 50 or 100 mg/kg diethylnitrosamine (DEN). Six control animals received only vehicle. Blood was collected to determine hepatic enzyme levels. Animals were divided into three groups: control (CO), precancerous lesions (PL), and advanced HCC. Liver samples were obtained for immunohistochemical analyses and the measurement of protein expression. Statistical analyses included Tukey's test and Pearson's correlation analyses. We observed an extensive ductular reaction in advanced HCC and a strong correlation between PCK7 and levels of γGT and the poor prognosis and aggressiveness of HCC. The extent of PCK7 and high γGT levels were associated with overexpression of inducible nitric oxide synthase (iNOS) and heat shock factor protein 1 (HSF-1). However, PCK7 and γGT levels were negatively correlated with protein expression of nuclear factor erythroid 2-related factor 2 (NRF2) and inducible heat shock protein 70 (iHSP70). These findings suggest that ductular reaction is involved in the progression of multistage hepatocarcinogenesis.
authors.affiliation: Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, RS, Brazil.|Department of Biological Sciences: Physiology, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite, 500, Porto Alegre, RS, Brazil.|Department of Physical Therapy of Porto Alegre Institute, IPA, Rua Joaquim Pedro Salgado, 80, Porto Alegre, Brazil.
authors.forename: Andrea Janz
authors.initials: AJ
authors.lastname: Moreira
authors.affiliation: Gene Therapy Center, Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, Brazil.
authors.forename: Graziella Ramos
authors.initials: GR
authors.lastname: Rodrigues
authors.affiliation: Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, RS, Brazil.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bona
authors.affiliation: Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, RS, Brazil.
authors.forename: Leila Xavier Sinigaglia
authors.initials: LX
authors.lastname: Fratta
authors.affiliation: Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, RS, Brazil.
authors.forename: Giovana Regina
authors.initials: GR
authors.lastname: Weber
authors.affiliation: Program in Cell and Molecular Biology Applied to Health, Universidade Luterana do Brasil, Av. Farroupilha, 8001, Canoas, Brazil.
authors.forename: Jaqueline Nascimento
authors.initials: JN
authors.lastname: Picada
authors.affiliation: Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, RS, Brazil.|Pediatric Hepatology Unit, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, Brazil.
authors.forename: Jorge Luiz
authors.initials: JL
authors.lastname: Dos Santos
authors.affiliation: Department of Pathology, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Carlos Thadeu
authors.initials: CT
authors.lastname: Cerski
authors.affiliation: Program in Liver Diseases, Universidade Federal de Ciências da Saúde de Porto Alegre, Rua Sarmento Leite, 245, Porto Alegre, Brazil.
authors.forename: Claudio Augusto
authors.initials: CA
authors.lastname: Marroni
authors.affiliation: Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, RS, Brazil. normap.marroni@gmail.com.|Department of Biological Sciences: Physiology, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite, 500, Porto Alegre, RS, Brazil. normap.marroni@gmail.com.|Program in Cell and Molecular Biology Applied to Health, Universidade Luterana do Brasil, Av. Farroupilha, 8001, Canoas, Brazil. normap.marroni@gmail.com.|, Rua José Kanan Aranha 102, 91760-470, Porto Alegre, RS, Brazil. normap.marroni@gmail.com.
authors.forename: Norma Possa
authors.initials: NP
authors.lastname: Marroni
mesh_terms: D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D020552:Comet Assay; D053552:Keratin-7 / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D017208:Rats, Wistar; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
chemical_list: D053552:Keratin-7; D009363:Neoplasm Proteins; D005723:gamma-Glutamyltransferase
keywords: Diethylnitrosamine; Gamma-glutamyl transferase; Hepatocellular carcinoma