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

Cassano, Marco; Offner, Sandra; Planet, Evarist; Piersigilli, Alessandra; Jang, Suk Min; Henry, Hugues; Geuking, Markus; Mooser, Catherine; McCoy, Kathleen; Macpherson, Andrew; Trono, Didier (2017). Polyphenic trait promotes liver cancer in a model of epigenetic instability in mice. Hepatology, 66(1), pp. 235-251. Wiley Interscience 10.1002/hep.29182

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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).

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Gastroenterology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie

UniBE Contributor:

Piersigilli, Alessandra; Geuking, Markus; Mooser, Catherine; McCoy, Kathleen and Macpherson, Andrew

Subjects:

600 Technology > 630 Agriculture
600 Technology > 610 Medicine & health

ISSN:

0270-9139

Publisher:

Wiley Interscience

Language:

English

Submitter:

Thi Thao Anh Pham

Date Deposited:

30 Jan 2018 14:11

Last Modified:

30 Jan 2018 14:11

Publisher DOI:

10.1002/hep.29182

PubMed ID:

28370258

BORIS DOI:

10.7892/boris.110283

URI:

https://boris.unibe.ch/id/eprint/110283

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