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Title: Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development

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. - Highlights: • Fgl1 knockout mice (Fgl1KO) are more prone to carcinogen-induced liver cancer compared to wildmore » type (WT) mates. • Tumors from the Fgl1KO are molecularly distinct with enhanced Akt and mTOR activity in comparison with Fgl1WT tumors. • Tumors from the Fgl1KO have enhanced expression of Trim35 and Tnfrsf10b, putative HCC tumor suppressors.« less
Authors:
; ;  [1] ;  [2] ;  [3] ;  [1] ;  [1]
  1. Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine. Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115 (United States)
  2. Department of Microbiology and Immunology, Harvard Medical School, Boston, MA 02115 (United States)
  3. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115 (United States)
Publication Date:
OSTI Identifier:
22458547
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 465; Journal Issue: 2; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARCINOGENS; COMPARATIVE EVALUATIONS; FIBRINOGEN; HEPATOMAS; LIVER; MICE; PHENOBARBITAL; PHENOTYPE; RADIOPROTECTIVE SUBSTANCES; RECEPTORS