PMID- 27525410 OWN - NLM STAT- MEDLINE DCOM- 20170327 LR - 20220330 IS - 1615-6102 (Electronic) IS - 0033-183X (Linking) VI - 254 IP - 2 DP - 2017 Mar TI - Ductular reaction, cytokeratin 7 positivity, and gamma-glutamyl transferase in multistage hepatocarcinogenesis in rats. PG - 911-920 LID - 10.1007/s00709-016-1000-0 [doi] AB - 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 (gammaGT) 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 gammaGT 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 gammaGT and the poor prognosis and aggressiveness of HCC. The extent of PCK7 and high gammaGT levels were associated with overexpression of inducible nitric oxide synthase (iNOS) and heat shock factor protein 1 (HSF-1). However, PCK7 and gammaGT 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. FAU - Moreira, Andrea Janz AU - Moreira AJ AD - Center of Experimental Research, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, RS, Brazil. AD - Department of Biological Sciences: Physiology, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite, 500, Porto Alegre, RS, Brazil. AD - Department of Physical Therapy of Porto Alegre Institute, IPA, Rua Joaquim Pedro Salgado, 80, Porto Alegre, Brazil. FAU - Rodrigues, Graziella Ramos AU - Rodrigues GR AD - Gene Therapy Center, Center of Experimental Research, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, Brazil. FAU - Bona, Silvia AU - Bona S AD - Center of Experimental Research, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, RS, Brazil. FAU - Fratta, Leila Xavier Sinigaglia AU - Fratta LX AD - Center of Experimental Research, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, RS, Brazil. FAU - Weber, Giovana Regina AU - Weber GR AD - Center of Experimental Research, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, RS, Brazil. FAU - Picada, Jaqueline Nascimento AU - Picada JN AD - Program in Cell and Molecular Biology Applied to Health, Universidade Luterana do Brasil, Av. Farroupilha, 8001, Canoas, Brazil. FAU - Dos Santos, Jorge Luiz AU - Dos Santos JL AD - Center of Experimental Research, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, RS, Brazil. AD - Pediatric Hepatology Unit, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, Brazil. FAU - Cerski, Carlos Thadeu AU - Cerski CT AD - Department of Pathology, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. FAU - Marroni, Claudio Augusto AU - Marroni CA AD - Program in Liver Diseases, Universidade Federal de Ciencias da Saude de Porto Alegre, Rua Sarmento Leite, 245, Porto Alegre, Brazil. FAU - Marroni, Norma Possa AU - Marroni NP AD - Center of Experimental Research, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos, 2400, Porto Alegre, RS, Brazil. normap.marroni@gmail.com. AD - Department of Biological Sciences: Physiology, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite, 500, Porto Alegre, RS, Brazil. normap.marroni@gmail.com. AD - Program in Cell and Molecular Biology Applied to Health, Universidade Luterana do Brasil, Av. Farroupilha, 8001, Canoas, Brazil. normap.marroni@gmail.com. AD - , Rua Jose Kanan Aranha 102, 91760-470, Porto Alegre, RS, Brazil. normap.marroni@gmail.com. LA - eng PT - Journal Article DEP - 20160815 PL - Austria TA - Protoplasma JT - Protoplasma JID - 9806853 RN - 0 (Keratin-7) RN - 0 (Neoplasm Proteins) RN - EC 2.3.2.2 (gamma-Glutamyltransferase) SB - IM MH - Animals MH - Blotting, Western MH - Carcinogenesis/*metabolism/pathology MH - Carcinoma, Hepatocellular/*metabolism/*pathology MH - Comet Assay MH - Keratin-7/*metabolism MH - Liver/pathology MH - Liver Neoplasms, Experimental/*metabolism/*pathology MH - Male MH - Neoplasm Proteins/metabolism MH - Neoplasm Staging MH - Rats, Wistar MH - gamma-Glutamyltransferase/*metabolism OTO - NOTNLM OT - Diethylnitrosamine OT - Gamma-glutamyl transferase OT - Hepatocellular carcinoma EDAT- 2016/08/16 06:00 MHDA- 2017/03/28 06:00 CRDT- 2016/08/16 06:00 PHST- 2015/10/31 00:00 [received] PHST- 2016/06/22 00:00 [accepted] PHST- 2016/08/16 06:00 [pubmed] PHST- 2017/03/28 06:00 [medline] PHST- 2016/08/16 06:00 [entrez] AID - 10.1007/s00709-016-1000-0 [pii] AID - 10.1007/s00709-016-1000-0 [doi] PST - ppublish SO - Protoplasma. 2017 Mar;254(2):911-920. doi: 10.1007/s00709-016-1000-0. Epub 2016 Aug 15.