Abstract
Mounting evidence indicates that S-Phase Kinase-Associated Protein 2 (SKP2) is overexpressed in human hepatocellular carcinoma (HCC). However, the role of SKP2 in hepatocarcinogenesis remains poorly delineated. To elucidate the function(s) of SKP2 in HCC, we stably overexpressed the SKP2 gene in the mouse liver, either alone or in combination with activated forms of N-Ras (N-RasV12), AKT1 (myr-AKT1), or β-catenin (ΔN90-β-catenin) protooncogenes, via hydrodynamic gene delivery. We found that forced overexpression of SKP2, N-RasV12 or ΔN90-β-catenin alone as well as co-expression of SKP2 and ΔN90-β-catenin did not induce liver tumor development. Overexpression of myr-AKT1 alone led to liver tumor development after long latency. In contrast, co-expression of SKP2 with N-RasV12 or myr-AKT1 resulted in early development of multiple hepatocellular tumors in all SKP2/N-RasV12 and SKP2/myr-AKT1 mice. At the molecular level, preneoplastic and neoplastic liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice exhibited a strong induction of AKT/mTOR and Ras/MAPK pathways. Noticeably, the tumor suppressor proteins whose levels have been shown to be downregulated by SKP2-dependent degradation in various tumor types, including p27, p57, Dusp1, and Rassf1A were not decreased in liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice. In human HCC specimens, nuclear translocation of SKP2 was associated with activation of the AKT/mTOR and Ras/MAPK pathways, but not with β-catenin mutation or activation. Altogether, the present data indicate that SKP2 cooperates with N-Ras and AKT proto-oncogenes to promote hepatocarcinogenesis in vivo.
Highlights
Human hepatocellular carcinoma (HCC) is the most frequent primary tumor of the liver and the fifth most common cancer worldwide [1,2,3]
Gene silencing by promoter hypermethylation seems to play a major role in the inactivation of tumor suppressor genes in liver cancer [9,10,11], emerging evidence indicates a post-transcriptional regulation of cell cycle negative modulators by the S-phase kinaseassociated protein 1 (SKP1)/CUL1/F-box protein (SCF) complex, an ubiquitin ligase implicated in the G1-S transition regulation, in this tumor type [12,13,14,15]
To determine whether S-Phase Kinase-Associated Protein 2 (SKP2) contributes to hepatocarcinogenesis in vivo, we hydrodynamically delivered the pT3-EF1α-HA-SKP2 plasmid to the mouse liver either alone or in combination with an oncogenic form of human neuroblastoma viral oncogene homolog (N-Ras) (N-RasV12)
Summary
Human hepatocellular carcinoma (HCC) is the most frequent primary tumor of the liver and the fifth most common cancer worldwide [1,2,3]. It has been shown that SKP2 nuclear accumulation directly correlates with clinical aggressiveness of HCC and is associated with shorter survival of liver cancer patients [15] In this tumor type, disruption of the negative control operated by kinesin family member 14 (KIF14) on SKP2 seems to be responsible for SKP2 unconstrained activity [22]. In vitro data suggest that hepatitis B virus (HBV) core promoter mutations might contribute to HBV associated liver cancer development by SKP2-dependent degradation of the p21WAF1 tumor suppressor gene [23]. These observations suggest a crucial role of SKP2 in hepatocarcinogenesis. It remains to be determined whether SKP2 contributes to liver tumor development and/or progression in vivo
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