title: Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development.
abstract: Fibrinogen like protein-1 (Fgl1) is a predominantly liver expressed protein that has been implicated as both a hepatoprotectant and a hepatocyte mitogen. Fgl1 expression is decreased in hepatocellular carcinoma (HCC) and its loss correlates with a poorly differentiated phenotype. To better elucidate the role of Fgl1 in hepatocarcinogenesis, we treated mice wild type or null for Fgl1 with diethyl nitrosamine and monitored for incidence of hepatocellular cancer. We find that mice lacking Fgl1 develop HCC at more than twice the rate of wild type mice. We show that hepatocellular cancers from Fgl1 null mice are molecularly distinct from those of the wild type mice. In tumors from Fgl1 null mice there is enhanced activation of Akt and downstream targets of the mammalian target of rapamycin (mTOR). In addition, there is paradoxical up regulation of putative hepatocellular cancer tumor suppressors; tripartite motif-containing protein 35 (Trim35) and tumor necrosis factor super family 10b (Tnfrsf10b). Taken together, these findings suggest that Fgl1 acts as a tumor suppressor in hepatocellular cancer through an Akt dependent mechanism and supports its role as a potential therapeutic target in HCC.
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hamed
authors.initials: H
authors.lastname: Nayeb-Hashemi
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Anal
authors.initials: A
authors.lastname: Desai
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Valeriy
authors.initials: V
authors.lastname: Demchev
authors.affiliation: Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Cohen
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: cukomadu@partners.org.
authors.forename: Chinweike
authors.initials: C
authors.lastname: Ukomadu
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004052:Diethylnitrosamine; D005340:Fibrinogen / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C476403:Fgl1 protein, mouse; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C000599700:TRIM35 protein, mouse; C505640:Tnfrsf10b protein, mouse; D004052:Diethylnitrosamine; D005340:Fibrinogen; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Diethyl nitrosamine; Fibrinogen like protein-1; Hepatocellular carcinoma; Hepatoprotecatant; Mitogen