Oncotarget

Research Papers:

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

Salvatore Delogu, Chunmei Wang, Antonio Cigliano, Kirsten Utpatel, Marcella Sini, Thomas Longerich, Nina Waldburger, Kai Breuhahn, Lijie Jiang, Silvia Ribback, Frank Dombrowski, Matthias Evert, Xin Chen and Diego F. Calvisi _

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Oncotarget. 2015; 6:2222-2234. https://doi.org/10.18632/oncotarget.2945

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Abstract

Salvatore Delogu1,*, Chunmei Wang2,*, Antonio Cigliano1, Kirsten Utpatel1, Marcella Sini1, Thomas Longerich3, Nina Waldburger3, Kai Breuhahn3, Lijie Jiang2, Silvia Ribback1, Frank Dombrowski1, Matthias Evert1, Xin Chen2 and Diego F. Calvisi1

1 Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany

2 Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA

3 Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

* These authors contributed equally to this work

Correspondence:

Xin Chen, email:

Diego F. Calvisi, email:

Keywords: SKP2, AKT, Ras, Hepatocellular carcinoma

Received: September 23, 2014 Accepted: December 09, 2014 Published: December 10, 2014

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.


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