Common, Unique and Systemic Signatures in gender-dependent hepatic tumorigenesis: a TMT-based quantitative proteomic analysis

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: lihuan Qin  

LAB HEAD: Aiguo Wang

PROVIDER: PXD012410 | Pride | 2021-09-08

REPOSITORIES: Pride