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.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and one of the severest malignancies dangerous for human’s health
We performed multiplexed isobaric TMT labeling combined with LCMS/Mass spectrometry (MS) approaches to quantify the proteome of tissues obtained from normal liver of wild-type (W) mice, hepatocellular carcinoma (T) and their paired adjacent precancerous (P) of Hras12V transgenic (Ras-Tg) mice in 9 months old male mice (9-M) and 15 months old female mice (15-F)
This study presents for the first time global proteomics data regarding Hras12V-induced hepatocarcinogenesis with gender disparity
Summary
HCC is the most common primary liver cancer and one of the severest malignancies dangerous for human’s health. Animal studies showed that male rodents are more susceptible to hepatocarcinogenesis that occurs either spontaneously or is chemically and oncogenetically induced as well as in experimental models of chronic viral infection [3,4,5] This indicates that there is a gender-dependent regulation of common molecular mechanisms leading to a predominance of HCC occurring in male humans and rodents [4]. We have established a transgenic mouse expressing the liver-specific Hras12V oncogene that develops liver cancer at the appropriate time and with high incidence in males but not in females [4] It is suitable for exploring the mechanisms about the ras oncogene-induced HCC and the malebiased hepatocarcinogenesis
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