title: 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.
authors.affiliation: Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Delogu
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cigliano
authors.affiliation: Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Utpatel
authors.affiliation: Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Sini
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Waldburger
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
authors.forename: Lijie
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ribback
authors.affiliation: Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.affiliation: Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institut für Pathologie, Universitätsmedizin Greifswald, Greifswald, Germany.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
mesh_terms: D000368:Aged; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010957:Plasmids / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D044786:S-Phase Kinase-Associated Proteins; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras)