title: AKT (v-akt murine thymoma viral oncogene homolog 1) and N-Ras (neuroblastoma ras viral oncogene homolog) coactivation in the mouse liver promotes rapid carcinogenesis by way of mTOR (mammalian target of rapamycin complex 1), FOXM1 (forkhead box M1)/SKP2, and c-Myc pathways.
abstract: Activation of v-akt murine thymoma viral oncogene homolog (AKT) and Ras pathways is often implicated in carcinogenesis. However, the oncogenic cooperation between these two cascades in relationship to hepatocellular carcinoma (HCC) development remains undetermined. To investigate this issue, we generated a mouse model characterized by combined overexpression of activated forms of AKT and neuroblastoma Ras viral oncogene homolog (N-Ras) protooncogenes in the liver by way of hydrodynamic gene transfer. The molecular mechanisms underlying crosstalk between AKT and N-Ras were assessed in the mouse model and further evaluated in human and murine HCC cell lines. We found that coexpression of AKT and N-Ras resulted in a dramatic acceleration of liver tumor development when compared with mice overexpressing AKT alone, whereas N-Ras alone did not lead to tumor formation. At the cellular level, concomitant up-regulation of AKT and N-Ras resulted in increased proliferation and microvascularization when compared with AKT-injected mice. Mechanistic studies suggested that accelerated hepatocarcinogenesis driven by AKT and N-Ras resulted from a strong activation of mammalian target of rapamycin complex 1 (mTORC1). Furthermore, elevated expression of FOXM1/SKP2 and c-Myc also contributed to rapid tumor growth in AKT/Ras mice, yet by way of mTORC1-independent mechanisms. The biological effects of coactivation of AKT and N-Ras were then recapitulated in vitro using HCC cell lines, which supports the functional significance of mTORC1, FOXM1/SKP2, and c-Myc signaling cascades in mediating AKT and N-Ras-induced liver tumor development.
  
  
  CONCLUSIONS
  Our data demonstrate the in vivo crosstalk between the AKT and Ras pathways in promoting liver tumor development, and the pivotal role of mTORC1-dependent and independent pathways in mediating AKT and Ras induced hepatocarcinogenesis.
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, USA.
authors: Coral
authors: C
authors: Ho
authors: Chunmei
authors: C
authors: Wang
authors: Sandra
authors: S
authors: Mattu
authors: Giulia
authors: G
authors: Destefanis
authors: Sara
authors: S
authors: Ladu
authors: Salvatore
authors: S
authors: Delogu
authors: Julia
authors: J
authors: Armbruster
authors: Lingling
authors: L
authors: Fan
authors: Susie A
authors: SA
authors: Lee
authors: Lijie
authors: L
authors: Jiang
authors: Frank
authors: F
authors: Dombrowski
authors: Matthias
authors: M
authors: Evert
authors: Xin
authors: X
authors: Chen
authors: Diego F
authors: DF
authors: Calvisi
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008113:Liver Neoplasms / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C546843:mTOR protein, mouse; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras)