Vascular invasion is considered as the critical risk factor of
hepatocellular carcinoma (HCC). To reveal the molecular mechanisms underlying macrovascular invasion (MaVI) in HCC, we performed an iTRAQ based proteomic study to identify notably dysregulated
proteins from eight HCC patients with differential vascular invasion and further confirmed them in the other 53 HCC patients. Forty-seven
proteins were found significantly down-regulated in HCC with MaVI. More importantly, 30 of them were not changed in HCC without MaVI. Gene ontology analysis of these 47
proteins shows the top three enriched biological processes are
urea cycle, gluconeogenesis, and
arginine biosynthetic process. We validated nine remarkably dysregulated candidates in HCC patients with MaVI by Western blot including eight down-regulated
proteins (CPS1, ASS1, ASL, ARG1, BHMT, DMGDH,
Annexin A6, and CES1) and one up-regulated
protein (CKAP4). Furthermore, dysregulation of CPS1, ASL, and ARG1, key
enzymes involved in
urea cycle, together with
Annexin A6 and CES1, major
proteins in regulating
cholesterol homeostasis and
fatty acid ester metabolism, was verified using immunohistochemical staining. The significant down-regulation of
urea cycle generates clinically relevant proteomic signature in HCC patients with macrovascular invasion, which may provide possible insights into the molecular mechanisms of
metastasis and new therapeutic targets of HCC.