Co-Upregulation of 14-3-3ζ and P-Akt is Associated with Oncogenesis and Recurrence of Hepatocellular Carcinoma.

BACKGROUND/AIMS: 14-3-3ζ is involved in the regulation of PI3K/Akt pathway which is closely associated with carcinogenesis. However, the clinical significance of combined detection of 14-3-3ζ and p-Akt in hepatocellular carcinoma (HCC) remains unclear.

METHODS: Two-hundred pairs of HCC and adjacent liver specimens were subjected to tissue microarray. The association of 14-3-3ζ and p-Akt levels with the postoperative survival and recurrence in HCC patients was analyzed with univariate and multivariate methods. Moreover, the effects of 14-3-3ζ overexpression on the growth of HCC and the expressions of p-Akt and HIF-1α were assessed in a xenograft mouse model.

RESULTS: Elevated levels of 14-3-3ζ and p-Akt were detected in HCC and a positive correlation between the levels of 14-3-3ζ and p-Akt was verified. HCC patients with satellite nodules, microvascular invasion, portal vein tumor thrombosis, poor tumor differentiation and an advanced tumor stage tended to have higher levels of 14-3-3ζ and p-Akt. In addition, the postoperative 3-, 5-, and 7-year overall survival rates in HCC patients with 14-3-3ζhigh and p-Akthigh were significantly lower compared with those with 14-3-3ζlow and p-Aktlow, and the cumulative recurrence rate in HCC patients with 14-3-3ζhigh and p-Akthigh was significantly higher than that in those with 14-3-3ζlow and p-Aktlow. The multivariate Cox proportional hazard analysis indicated that concomitant upregulation of 14-3-3ζ and p-Akt was an independent factor that predicted poor survival and high recurrence in HCC patients. Furthermore, animal experiment showed that overexpression of 14-3-3ζ accelerated the growth of HCC xenograft tumors and induced the expressions of p-Akt and HIF-1α in vivo.

CONCLUSION: Co-upregulation of 14-3-3ζ and p-Akt predicts poor prognosis in patients with HCC, and 14-3-3ζ-induced activation of the Akt signaling pathway contributes to HCC progression.