Activation of the SKP2 protooncogene is a common effector pathway in hepatocarcinogenesis and contributes to malignant transformation of the liver

We have recently shown that upregulation of SKP2 protooncogene is associated with the development and progression of human hepatocellular carcinoma (HCC). In the present study, we further investigated the functional role of SKP2 by using in vitro and in vivo approaches. Forced overexpression of a number of known liver oncogenes, including AKT, E2F1, N-Ras, ERK2, STAT5b, and mutated beta-catenin in human HCC cell lines led to increased proliferation, which was associated with the rise in the levels and activation of SKP2 (as assessed by SKP2-mediated degradation of p27, p57, and p130 target genes). Although the protooncogene FOXM1 has been shown to transcriptionally activate SKP2, induction of SKP2 was mediated by FOXM1 only in N-Ras- and ERK2-overexpressing cells. On the other hand, the growth promoting effects driven by AKT, ERK2, E2F1, N-Ras, STAT5b, and mutated beta-catenin overexpression in vitro were significantly decreased when their overexpression was paralleled by siRNA mediated silencing of SKP2. Forced induction of SKP2 gene via hydrodynamic gene delivery did not induce significant morphologic alterations in the mouse liver, similar to that occurring in mice transfected with the N-Ras gene. However, when SKP2 and N-Ras genes were co-injected via hydrodynamic transfection, preneoplastic liver lesions developed, which finally evolved to HCC 18 weeks after injection. Furthermore, SKP2 accelerated hepatocarcinogenesis induced by the AKT protooncogene when both genes were co-injected in the mouse liver. In conclusion, the in vitro and in vivo data obtained in this study provide solid evidence that SKP2 functions as an oncogene in liver cancer, acting downstream of many signaling pathways involved in human HCC development. Therapeutic approaches aimed at inhibiting SKP2 might be highly beneficial for the treatment of human HCC.

AKT - E2F1 - ERK2 - FOXM1 - HCC - Hepatocarcinogenesis - N-Ras - SKP2 - Stat5b - beta-catenin - hydrodynamic gene delivery - p130 - p27 - p57