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Title: Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice

Farnesoid X receptor (FXR, Nr1h4) and small heterodimer partner (SHP, Nr0b2) are nuclear receptors that are critical to liver homeostasis. Induction of SHP serves as a major mechanism of FXR in suppressing gene expression. Both FXR{sup −/−} and SHP{sup −/−} mice develop spontaneous hepatocellular carcinoma (HCC). SHP is one of the most strongly induced genes by FXR in the liver and is a tumor suppressor, therefore, we hypothesized that deficiency of SHP contributes to HCC development in the livers of FXR{sup −/−} mice and therefore, increased SHP expression in FXR{sup −/−} mice reduces liver tumorigenesis. To test this hypothesis, we generated FXR{sup −/−} mice with overexpression of SHP in hepatocytes (FXR{sup −/−}/SHP{sup Tg}) and determined the contribution of SHP in HCC development in FXR{sup −/−} mice. Hepatocyte-specific SHP overexpression did not affect liver tumor incidence or size in FXR{sup −/−} mice. However, SHP overexpression led to a lower grade of dysplasia, reduced indicator cell proliferation and increased apoptosis. All tumor-bearing mice had increased serum bile acid levels and IL-6 levels, which was associated with activation of hepatic STAT3. In conclusion, SHP partially protects FXR{sup −/−} mice from HCC formation by reducing tumor malignancy. However, disrupted bile acid homeostasis by FXRmore » deficiency leads to inflammation and injury, which ultimately results in uncontrolled cell proliferation and tumorigenesis in the liver. - Highlights: • SHP does not prevent HCC incidence nor size in FXR KO mice but reduces malignancy. • Increased SHP promotes apoptosis. • Bile acids and inflammation maybe critical for HCC formation with FXR deficiency.« less
Authors:
 [1] ;  [2] ;  [3] ;  [2] ;  [4] ;  [5] ;  [6] ;  [5] ;  [7] ;  [8] ;  [2]
  1. Department of Surgical Oncology, Cancer Treatment Center, The Fourth Affiliated Hospital of Harbin Medical University, Harbin (China)
  2. Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, NJ (United States)
  3. Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing (China)
  4. (United States)
  5. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)
  6. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS (United States)
  7. Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI (United States)
  8. Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT (United States)
Publication Date:
OSTI Identifier:
22285422
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 272; Journal Issue: 2; Other Information: Copyright (c) 2013 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; APOPTOSIS; BILE ACIDS; CELL PROLIFERATION; HEPATOMAS; INFLAMMATION; INJURIES; LIVER; LIVER CELLS; MICE; RECEPTORS