2. Academic Validation
  3. RB tumor suppressive function in response to xenobiotic hepatocarcinogens

RB tumor suppressive function in response to xenobiotic hepatocarcinogens

  • Am J Pathol. 2014 Jun;184(6):1853-9. doi: 10.1016/j.ajpath.2014.02.025.
Christopher Reed 1,  Jack Hutcheson 2,  Christopher N Mayhew 3,  Agnieszka K Witkiewicz 4,  Erik S Knudsen 5
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • 2 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
  • 3 Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
  • 4 Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
  • 5 Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: erik.knudsen@utsouthwestern.edu.
PMID: 24726645 DOI: 10.1016/j.ajpath.2014.02.025
Abstract

Diverse etiologic events are associated with the development of hepatocellular carcinoma. During hepatocarcinogenesis, genetic events likely occur that subsequently cooperate with long-term exposures to further drive the progression of hepatocellular carcinoma. In this study, the frequent loss of the retinoblastoma (RB) tumor suppressor in hepatocellular carcinoma was modeled in response to diverse hepatic stresses. Loss of RB did not significantly affect the response to a steatotic stress as driven by a methionine- and choline-deficient diet. In addition, RB status did not significantly influence the response to peroxisome proliferators that can drive hepatomegaly and tumor development in rodents. However, RB loss exhibited a highly significant effect on the response to the xenobiotic1,4-Bis-[2-(3,5-dichloropyridyloxy)] benzene. Loss of RB yielded a unique proliferative response to this agent, which was distinct from both regenerative stresses and genotoxic carcinogens. Long-term exposure to 1,4-Bis-[2-(3,5-dichloropyridyloxy)] benzene yielded profound tumor development in RB-deficient livers that was principally absent in RB-sufficient tissue. These data demonstrate the context specificity of RB and the key role RB plays in the suppression of hepatocellular carcinoma driven by xenobiotic stress.

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