title: MicroRNA-224 upregulation and AKT activation synergistically predict poor prognosis in patients with hepatocellular carcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 302 Hospital of PLA, Beijing 100039, China.
authors.forename: Lingxiang
authors.initials: L
authors.lastname: Yu
authors.affiliation: 302 Hospital of PLA, Beijing 100039, China.
authors.forename: Jiabin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 302 Hospital of PLA, Beijing 100039, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Guo
authors.affiliation: 302 Hospital of PLA, Beijing 100039, China. Electronic address: lizhiwei112013@163.com.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: 302 Hospital of PLA, Beijing 100039, China. Electronic address: peiruizhang2013@163.com.
authors.forename: Peirui
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018450:Disease Progression; D018572:Disease-Free Survival; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C546140:MIRN224 microRNA, human; D035683:MicroRNAs; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; Hepatocellular carcinoma; Microrna-224; Prognosis; Tumor progression