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Kap1 in liver physiology

ABSTRACT: Hepatocellular carcinoma (HCC) represents the fifth most common form of cancer worldwide and carries a high mortality rate due to lack of effective treatment. Males are eight times more likely to develop HCC that females, an effect largely driven by sex hormones, albeit through still poorly understood mechanisms. We previously identified TRIM28, a scaffold protein capable of recruiting a number of chromatin modifiers, as a crucial mediator of sexual dimorphism in the liver, with Trim28hep-/- mice displaying 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 ageing 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. This work underpins how discrete polyphenic traits in epigenetically unstable conditions can contribute to a cancer-prone state, and more broadly provides new evidence linking hormonal imbalances, metabolic disturbances, gut microbiota and cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE86389 | GEO | 2017/08/22

SECONDARY ACCESSION(S): PRJNA341592

REPOSITORIES: GEO

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Project description:Hepatocellular carcinoma (HCC) is the most common liver cancer and a highly malignant tumor. The frequent activation of Ras signaling pathway and the male prevalence are the distinct characteristics of HCC though the underlying mechanisms remain elucidated. By exploring a mouse model of HCC induced by hepatocyte-specific expression of the Hras12V oncogene and showed significant male prevalence in hepatic tumorigenesis, we performed a high-throughput comparative proteomic analysis based on tandem-mass-tag (TMT) labeling combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) on the protein samples from hepatic tumor tissues (T) and peri-tumor tissues (P) of transgenic males and females and the corresponding normal liver tissues (W) of non-transgenic males and females. In total, 5733 proteins were confidently identified, of which 5193 proteins were quantified. Finally, 1344 differentially expressed proteins (DEPs) (quantified in all examined samples; 1.5 ≤ quantitative ratios ≤ 0.67; p ≤ 0.05) were selected for further analysis. Vertical comparison within W, P, T of males and females, respectively, showed that the numbers of DEPs in males were much higher than females. Bioinformatics analyses showed the common and unique cluster enriched items between sexes which indicates the common and gender disparity pathways towards HCC. Further expression change pattern analysis revealed HCC positive/negative-related and Ras oncogene positive/negative-related DEPs. Horizontal comparison between males and females showed that Ras oncogene gradually and significantly reduced the responses to sex hormones from hepatocytes to hepatoma cells and therefore shrunk their gender disparity, which may contribute to the cause of the loss of HCC clinical responses to the therapeutic approaches targeting sex hormone pathways. Additionally, FABP5 was found to be a more sensitive biomarker for clinical diagnose and prognosis prediction of HCC patients comparing to AFP. In conclusion, the present study firstly provided a comprehensive proteome profiles and novel insights in male bias hepatic tumorigenesis induced by H-ras12V oncogene.

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Kap1 in liver physiology

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