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).
Polyphenic trait promote liver cancer in a model of epigenetic instability / M. Cassano, S. Offner, E. Planet, A. Piersigilli, S. Jang, H. Henry, C. Mooser, K. Mccoy, A. Mcpherson, D. Trono. - In: HEPATOLOGY. - ISSN 0270-9139. - 66:1(2017 Jul), pp. 235-251.
|Titolo:||Polyphenic trait promote liver cancer in a model of epigenetic instability|
|Settore Scientifico Disciplinare:||Settore BIO/17 - Istologia|
|Data di pubblicazione:||lug-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1002/hep.29182|
|Appare nelle tipologie:||01 - Articolo su periodico|