*Purpose: Hepatocellular Carcinoma (HCC) is the 2nd and fastest-growing cause of cancer related mortality worldwide, mainly from the metabolic cellular disturbances promoted by the epidemic of obesity and a lack of markers for its early detection. Our group has identified a novel signaling pathway, comprising of the α1-Na/K-ATPase (NKA), Caveolin-1 (Cav-1) and Src kinase (Src) which is necessary for cell development and function. In carcinogenesis, regulation of Src-phosphorylation by the α1-subunit of the Na/K-ATPase at caveola may initiate protein interactions, beginning at Cav-1 in the plasma membrane that leads to a disequilibrium in the SMAC-Survivin apoptotic signaling in the cell, resulting in a pathogenic “apoptotic switch” that favors HCC tumorigenesis. We propose that these interactions are relayed via the PI3K- Akt- S6K1 and the EGFR- STAT 3 signaling pathways from cell membrane to its interior. We hypothesize inhibition of α1-Na/K-ATPase-CAV-1-Src signaling as putative target for the treatment of HCC.

*Methods: Expression of Cav-1/SMAC-Diablo/Survivin proteins was performed by confocal-microscopy on immuno-stained livers from HCC, NASH and normal human subjects, and rodent models. NASH and HCC mice were exposed to doses of pNaKtide, an inhibitor of Scr-phosphorylation at the NKA α1-caveolin-1 complex. Significant differences among groups were established at p<0.05 using ANOVA/t-test.

*Results: The expression of Cav-1 was significantly higher in liver tissue from patients with NASH±HCC vs normal livers or livers with metastases (p<0.05). Survivin expression was significantly higher in patients with NASH/HCC+ vs NASH/HCC-, normal livers, and liver with metastases (p<0.05). In contrast, SMAC protein expression was significantly lower in liver tissue with NASH or HCC vs controls. Similar results were obtained in the murine models. In mouse models, pNaKtide, significantly restored SMAC expression and attenuated Survivin expression in a dose-dependent manner (p<0.01). Also, in HCC murine model, pNaKtide treated groups showed a significantly dose- dependent lower tumor burden as well as fibrosis vs the untreated group(p<0.01). On the contrary, apoptosis increased significantly in pNaKtide treated groups vs untreated group (p<0.05).

*Conclusions: Cav-1, SMAC and Survivin proteins expression differed significantly in patients with HCC and NASH when compared to normal livers or livers with metastases. This observation was validated in NASH and HCC murine models. Inhibition α1-Na/K-ATPase-CAV-1-Src signaling pathway by pNaktide resulted in the reversal of the “oncogenic apoptotic switch”, leading to HCC prevention/ tumor regression.

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