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 via 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 co-expression 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 upregulation 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 via mTORC1-independent mechanisms. The biological effects of co-activation 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. Conclusion 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.

Delivery of miR-375 and doxorubicin hydrochloride by lipid-coated hollow mesoporous silica nanoparticles to overcome multiple drug resistance in hepatocellular carcinoma

“…Hydrodynamic injections were performed as reported previously. 33,34 In brief, FVB/N mice were injected with 5 μg myr-Akt/pT3EF1α, 5 μg NRasV12/pT2-Caggs, and 0.4 μg pCMV/SB in 2 mL saline via tail vein in 5-10 s. Upon injection, the Ras and Akt plasmid, along with transposase plasmid were taken up by hepatocytes and integrated into their chromosomes. The continuous overexpression of Ras and Akt induced the formation of tumor in the liver.…”

“…To mimic HCC pathology in human patients, a mouse model of Akt/ Ras-induced primary HCC was developed by administering a hydrodynamic injection of plasmids carrying the two genes into mice, as previously described. 33 In hepatocytes, Akt promotes lipogenesis, whereas Ras promotes mitosis. Therefore, the synergistic effects of these two genes lead to tumor formation in the liver ( Figure 8A).…”

Long Noncoding RNA HULC Modulates Abnormal Lipid Metabolism in Hepatoma Cells through an miR-9–Mediated RXRA Signaling Pathway

“…Notably, we observed that ACSL1 was able to promote the proliferation of hepatoma cells, suggesting that the role of ACSL1 in the promotion of cell proliferation might be associated with the disturbance of lipid metabolism mediated by ACSL1 in hepatoma cells. In addition, it has been reported that the AKT/mTOR cascade influences the growth, survival, metabolism, and migration of liver cancer cells, and the extent of aberrant lipogenesis is correlated with the activation of the AKT/mTOR signaling pathway (14,44). This relationship suggests that the AKT/ mTOR pathway plays a pivotal role in the deregulation of lipid metabolism in HCC.…”

Histone Chaperone CHAF1A Inhibits Differentiation and Promotes Aggressive Neuroblastoma

“…Ras signaling networks drive cellular proliferation and restrict differentiation, and previous studies have also suggested a role for RAS-MEK signaling in regulation of responses to retinoic acid in different cellular systems (46). Activation of NRAS seems to be critical in neuroblastoma tumorigenesis, considering its function in stabilizing MYCN, promoting MYCN-dependent cell cycle progression, and blocking p53-mediated cell cycle check points and proapoptotic effects (22,47).…”