Format

Send to

Choose Destination
Hepatology. 2017 Jul;66(1):235-251. doi: 10.1002/hep.29182. Epub 2017 May 18.

Polyphenic trait promotes liver cancer in a model of epigenetic instability in mice.

Author information

1
School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
2
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
3
Clinical Chemistry Laboratory, Lausanne University Hospital, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
4
Mucosal Immunology Lab, Department of Clinical Research, University of Bern, Bern, Switzerland.

Abstract

Hepatocellular carcinoma (HCC) represents the fifth-most common form of cancer worldwide and carries a high mortality rate attributed to lack of effective treatment. Males are 8 times more likely to develop HCC than females, an effect largely driven by sex hormones, albeit through still poorly understood mechanisms. We previously identified TRIM28 (tripartite protein 28), a scaffold protein capable of recruiting a number of chromatin modifiers, as a crucial mediator of sexual dimorphism in the liver. Trim28hep-/- mice display sex-specific transcriptional deregulation of a wide range of bile and steroid metabolism genes and development of liver adenomas in males. We now demonstrate that obesity and aging precipitate alterations of TRIM28-dependent transcriptional dynamics, leading to a metabolic infection state responsible for highly penetrant male-restricted hepatic carcinogenesis. Molecular analyses implicate aberrant androgen receptor stimulation, biliary acid disturbances, and altered responses to gut microbiota in the pathogenesis of Trim28hep-/- -associated HCC. Correspondingly, androgen deprivation markedly attenuates the frequency and severity of tumors, and raising animals under axenic conditions completely abrogates their abnormal phenotype, even upon high-fat diet challenge.

CONCLUSION:

This work underpins how discrete polyphenic traits in epigenetically metastable conditions can contribute to a cancer-prone state and more broadly provides new evidence linking hormonal imbalances, metabolic disturbances, gut microbiota, and cancer. (Hepatology 2017;66:235-251).

PMID:
28370258
PMCID:
PMC5518198
DOI:
10.1002/hep.29182
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center