title: Cytokeratin 7/19 expression in N-diethylnitrosamine-induced mouse hepatocellular lesions: implications for histogenesis.
abstract: Hepatocellular carcinoma (HCC) is a common malignancy with poor clinical outcome, whose histogenesis is the subject of intense debate. Specifically, expression of cytokeratins (CKs) 7 and 19, associated with aggressive biological behaviour, is proposed to reflect a possible progenitor cell origin or tumour dedifferentiation towards a primitive phenotype. This work addresses that problem by studying CKs 7 and 19 expression in N-diethylnitrosamine (DEN)-induced mouse HCCs. ICR mice were divided into six DEN-exposed and six matched control groups. Samples were taken from each group at consecutive time points. Hyperplastic foci (13 lesions) occurred at 29-40 weeks (groups 8, 10 and 12) with diffuse dysplastic areas (19 lesions) and with one hepatocellular adenoma (HCA) (at 29 weeks). HCCs (4 lesions) were observed 40 weeks after the first DEN administration (group 12). CKs 7 and 19 showed identical expression patterns and located to large, mature hepatocytes, isolated or in small clusters. Hyperplastic foci and the single HCA were consistently negative for both markers, while dysplastic areas and HCCs were positive. These results support the hypothesis that CKs 7 and 19 expression in hepatocellular malignancies results from a dedifferentiation process rather than from a possible progenitor cell origin.
authors.affiliation: Veterinary Sciences Department, University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Veterinary Science Department, Veterinary and Animal Science Research Centre (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal.
authors.forename: Nuno P
authors.initials: NP
authors.lastname: Santos
authors.forename: Paula A
authors.initials: PA
authors.lastname: Oliveira
authors.forename: Regina
authors.initials: R
authors.lastname: Arantes-Rodrigues
authors.forename: Ana I
authors.initials: AI
authors.lastname: Faustino-Rocha
authors.forename: Aura
authors.initials: A
authors.lastname: Colaço
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopes
authors.forename: Rui M
authors.initials: RM
authors.lastname: Gil da Costa
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004052:Diethylnitrosamine / Q000009:adverse effects; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D053539:Keratin-19 / Q000378:metabolism*; D053552:Keratin-7 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011230:Precancerous Conditions
chemical_list: D053539:Keratin-19; D053552:Keratin-7; D004052:Diethylnitrosamine
keywords: N-diethylnitrosamine; cytokeratin; hepatic progenitor cell; hepatocellular carcinoma; histogenesis; liver
references.citation: Int J Exp Pathol. 2009 Aug;90(4):367-86
references.pmid: 19659896
references.citation: Ann Hepatol. 2006 Jan-Mar;5(1):16-24
references.pmid: 16531960
references.citation: Gastroenterology. 2006 Apr;130(4):1117-28
references.pmid: 16618406
references.citation: Nat Med. 2006 Apr;12(4):410-6
references.pmid: 16532004
references.citation: Mol Cell Proteomics. 2004 Jan;3(1):73-81
references.pmid: 14593079
references.citation: J Hepatol. 2004 Feb;40(2):298-304
references.pmid: 14739102
references.citation: Cancer Res. 1989 Mar 1;49(5):1327-9
references.pmid: 2917362
references.citation: J Hepatol. 2000 Jul;33(1):76-84
references.pmid: 10905589
references.citation: J Cancer Res Clin Oncol. 1984;108(1):60-5
references.pmid: 6746718
references.citation: Carcinogenesis. 2002 Mar;23(3):435-45
references.pmid: 11895858
references.citation: Cancer Res. 1983 Sep;43(9):4253-9
references.pmid: 6871863
references.citation: Hepatology. 2005 Aug;42(2):353-61
references.pmid: 15965925
references.citation: Toxicol Pathol. 2011 Aug;39(5):776-86
references.pmid: 21628716
references.citation: J Hepatol. 2012 Jul;57(1):61-8
references.pmid: 22420978
references.citation: Histopathology. 2006 Aug;49(2):138-51
references.pmid: 16879391
references.citation: Hepatology. 2010 Apr;51(4):1401-9
references.pmid: 20054870
references.citation: Cancer Res. 2007 Dec 1;67(23):11141-6
references.pmid: 18056438
references.citation: J Hepatobiliary Pancreat Sci. 2011 Jul;18(4):537-43
references.pmid: 21234612
references.citation: World J Gastroenterol. 2001 Jun;7(3):335-9
references.pmid: 11819786
references.citation: Int J Cancer. 2010 Dec 15;127(12):2893-917
references.pmid: 21351269
references.citation: Cancer Sci. 2003 Oct;94(10):851-7
references.pmid: 14556657
references.citation: Histopathology. 1989 Aug;15(2):125-35
references.pmid: 2476370
references.citation: J Pathol. 2004 Nov;204(4):367-76
references.pmid: 15495250
references.citation: J Vet Med Sci. 2010 Mar;72(3):263-9
references.pmid: 20035116
references.citation: Histochem Cell Biol. 2008 Jun;129(6):735-49
references.pmid: 18443813
references.citation: Toxicol Appl Pharmacol. 2010 Jan 1;242(1):47-55
references.pmid: 19796649
references.citation: Hum Pathol. 1991 Feb;22(2):172-8
references.pmid: 1848205
references.citation: Environ Health Perspect. 1983 Apr;50:149-61
references.pmid: 6873010