SKP2 cooperates with N-Ras or AKT to induce liver tumor development in mice

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.

Targeting β‐catenin in hepatocellular cancers induced by coexpression of mutant β‐catenin and K‐Ras in mice

“…Indeed N-Ras, another Ras family member, cooperates with molecules like Sphase kinase-associated protein 2 or AKT in promoting HCC in similar SB models. (19,20) Ras activation was also observed in the hMet-mutant-b-catenin model. (12) In the current study, we observe Ras activation in the G12D-K-Ras-S45Y-b-catenin and G12D-K-Ras-S33Y-b-catenin groups.…”

“…In our current study, activated K‐Ras (G12D‐K‐Ras) expression by itself did not yield HCC, suggesting that it may cooperate with another signaling pathway in tumorigenesis. Indeed N‐Ras, another Ras family member, cooperates with molecules like S‐phase kinase‐associated protein 2 or AKT in promoting HCC in similar SB models . Ras activation was also observed in the hMet‐mutant‐β‐catenin model .…”

Down‐regulation of the cyclin‐dependent kinase inhibitor p57 is mediated by Jab1/Csn5 in hepatocarcinogenesis

“…The E3 ligase has been shown to be responsible for regulating the cellular level of p57 by ubiquitylation and proteolysis . Some evidence indicates that Skp2 could partly mediate p57 decreasing by a ubiquitin‐proteasome mechanism in HCC progression . Skp2 is responsible for regulating the cellular level of p57 via ubiquitylation by targeting p57 phosphorylated at mouse T329 (human p57 T310) .…”

“…(13) It has been reported that microRNAs, as well as the Akt and Skp2 pathways, can contribute to liver tumorigenicity, in part by p57 down-regulation. (14,15) However, the mechanism underlying p57 down-regulation in HCC has not been investigated to date.…”

Ubiquitin ligases in oncogenic transformation and cancer therapy

“…3a). Transgenic overexpression of Skp2 in the mouse prostate induces hyperplasia, dysplasia and low-grade carcinoma 31 , while co-expression of Skp2 with Nras G12V or myristoylated Akt1 in the mouse liver results in hepatocellular carcinoma (HCC) 32 . Conversely, Skp2 -knockout efficiently inhibits tumour development in a conditional Pten -deficient and Trp53 -deficient mouse prostate cancer model via activation of p27 KIP1 -dependent, p21 CIP1 -dependent and activating transcription factor 4 (ATF4)-dependent senescence 33 .…”