MicroRNA-224 upregulation and AKT activation synergistically predict poor prognosis in patients with hepatocellular carcinoma.

Previous evidence has shown that microRNA (miR)-224 may function as an onco-miRNA in hepatocellular carcinoma (HCC) cells by activating AKT signaling. However, little is known about the clinical significance of the combined expression of miR-224 and phosphorylated-AKT (pAKT) on human HCC. The aim of this study was to investigate the synergistical influence of miR-224 and pAKT on clinical characteristics and prognosis in patients with HCC. One-hundred and thirty HCC patients who had undergone curative liver resection were selected. In situ hybridization and immunohistochemistry were respectively performed to detect the expression of miR-224 and pAKT in the respective tumors. Compared with the adjacent nonneoplastic liver tissues, the expression levels of miR-224 and pAKT protein in HCC tissues were both significantly increased (both P<0.001). In addition, the combined upregulation of miR-224 and pAKT protein was significantly associated with serum AFP (P=0.01), tumor stage (P=0.002) and tumor grade (P=0.008). Moreover, HCC patients highly expressing both miR-224 and pAKT protein had worse 5-year disease-free survival and 5-year overall survival (both P<0.001). Furthermore, the Cox proportional hazards model showed that the combined upregulation of miR-224 and pAKT protein (miR-224-high/pAKT-high) may be independent poor prognostic factors for both 5-year disease-free survival (P=0.008) and 5-year overall survival (P=0.01) in HCC. These results indicate for the first time that miR-224 upregulation and AKT activation may synergistically associate with tumor progression of HCC. The combined high expression of miR-224 and pAKT may be a potential indicator for predicting unfavorable prognosis in HCC patients.