Differential proteomic analysis of gender-dependent hepatic tumorigenesis in Hras12V transgenic mice [Research]

Male prevalence is an outstanding characteristic of hepatocellular carcinoma (HCC), and the underlying mechanisms for this have remained largely unknown. In the present study, Hras12V transgenic mice, in which hepatocyte-specific expression of the ras oncogene induces male-biased hepatic tumorigenesis, were studied, and altered proteins were detected by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Protein samples from hepatic tumor tissues (T) and peri-tumor tissues (P) of transgenic males and females and the corresponding normal liver tissues (Wt) of non-transgenic males and females were subjected to pairwise comparisons based on proteomic analysis. Among 2381 auto-detected protein spots, more than 1600 were differentially expressed based on a pairwise comparison (|ratio| >= 1.5, p <= 0.05). Of these, 180 spots were randomly selected for matrix-assisted laser desorption ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF MS) identification; finally, 89 distinct proteins were obtained. Among these 89 proteins, 7 and 50 proteins were further validated by Western blotting and literature investigation, respectively. Intriguingly, compared to Wt, the altered proteins were relatively concentrated in T in transgenic females but in P in transgenic males. Consistently, the levels of p-ERK and p-mTOR were significantly higher in the T of females compared to that of males. The pathway enrichment assay showed that 5 pathways in males but only 1 in females were significantly altered in terms of the up-regulated proteins in T compared to Wt. These data indicate that female hepatocytes are disturbed by oncogenes with great difficulty, whereas male hepatoctyes readily do so. In addition, 33 proteins were gender-dependently altered in hepatic tumorigenesis. Moreover, 4% DNA packaging and 4% homeostasis-related functional proteins were found in females but not in males, and more nucleus proteins were found in females (8%) than in males (3%). In conclusion, the proteomic data and comparative analysis presented here offer crucial clues for elucidating the mechanisms that underlie the male prevalence in HCC.

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