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Proteomic analysis revealed common, unique and systemic signatures in gender-dependent hepatocarcinogenesis.

ABSTRACT: Hepatocellular carcinoma (HCC) is the most common liver cancer and is highly malignant. Male prevalence and frequent activation of the Ras signaling pathway are distinct characteristics of HCC. However, the underlying mechanisms remain to be elucidated. By exploring Hras12V transgenic mice showing male-biased hepatocarcinogenesis, 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 tissue samples obtained from HCC (T) and their paired adjacent precancerous (P) of Hras12V transgenic male and female mice (Ras-Tg) and normal liver (W) of wild-type male and female mice (Non-Tg). The further validation and investigation were performed using quantitative real-time PCR and western blot. Totally, 5193 proteins were quantified, originating from 5733 identified proteins. Finally, 1344 differentially expressed proteins (DEPs) (quantified in all examined samples; |ratios| ? 1.5, p < 0.05) were selected for further analysis. Comparison within W, P, and T of males and females indicated that the number of DEPs in males was much higher than that in females. Bioinformatics analyses showed the common and unique cluster-enriched items between sexes, indicating the common and gender-disparate pathways towards HCC. Expression change pattern analysis revealed HCC positive/negative-correlated and ras oncogene positive/negative-correlated DEPs and pathways. In addition, it showed that the ras oncogene gradually and significantly reduced the responses to sex hormones from hepatocytes to hepatoma cells and therefore shrunk the gender disparity between males and females, which may contribute to the cause of the loss of HCC clinical responses to the therapeutic approaches targeting sex hormone pathways. Additionally, gender disparity in the expression levels of key enzymes involved in retinol metabolism and terpenoid backbone/steroid biosynthesis pathways may contribute to male prevalence in hepatocarcinogenesis. Further, the biomarkers, SAA2, Orm2, and Serpina1e, may be sex differences. In conclusion, common and unique DEPs and pathways toward HCC initiated by ras oncogene from sexually dimorphic hepatocytes provide valuable and novel insights into clinical investigation and practice.

SUBMITTER: Li H

PROVIDER: S-EPMC7427087 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Proteomic analysis revealed common, unique and systemic signatures in gender-dependent hepatocarcinogenesis.

Li Huiling H Rong Zhuona Z Wang Hong H Zhang Nan N Pu Chunwen C Zhao Yi Y Zheng Xu X Lei Chuanyi C Liu Yang Y Luo Xiaoqin X Chen Jun J Wang Fujin F Wang Aiguo A Wang Jingyu J

Biology of sex differences 20200813 1

Hepatocellular carcinoma (HCC) is the most common liver cancer and is highly malignant. Male prevalence and frequent activation of the Ras signaling pathway are distinct characteristics of HCC. However, the underlying mechanisms remain to be elucidated. By exploring Hras12V transgenic mice showing male-biased hepatocarcinogenesis, we performed a high-throughput comparative proteomic analysis based on tandem-mass-tag (TMT) labeling combined with liquid chromatography-tandem mass spectrometry (LC- ...[more]

PMID: 32792008

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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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Proteomic analysis revealed common, unique and systemic signatures in gender-dependent hepatocarcinogenesis.

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Proteomic analysis revealed common, unique and systemic signatures in gender-dependent hepatocarcinogenesis.

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