MicroRNA-194 acts as a prognostic marker and inhibits proliferation in hepatocellular carcinoma by targeting MAP4K4

Int J Clin Exp Pathol. 2015 Oct 1;8(10):12446-54. eCollection 2015.

Abstract

MicroRNAs (miRNAs) play a crucial role in cancer development and progression of hepatocellular carcinoma (HCC). In this study, we aimed to analyze the role of microRNA-194 (miR-194) in HCC. We found that miR-194 expression was significantly reduced in HCC and its expression was an independent poor prognostic factor for HCC patient overall and disease-free survival rate. A significant correlation was observed between miR-194 reduction and unfavourable variables including tumor size (P = 0.0315), histologic grade (P = 0.0038), TNM stage (P = 0.0083), intrahepatic metastasis (P = 0.0184). Overexpression of miR-194 in HCC cell lines HepG2 and Hep3B inhibited cell proliferation by blocking G1-S transition and inducing apoptosis. Mitogen-activated protein kinase 4 (MAP4K4), a potential target gene of miR-194, was inversely correlated with miR-194 expression in HCC tissues and cell lines. Further studies demonstrated that miR-194 regulated the progression of HCC through directly inhibiting the expression of MAP4K4 and the restoration of MAP4K4 expression reversed the inhibitory effects of miR-194 on HCC cell proliferation. Together, our findings indicate that miR-194 may serve as a valuable prognostic marker and promising interventional therapeutic target for HCC.

Keywords: MAP4K4; hepatocellular carcinoma; interventional therapy; microRNA-194; proliferation.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Apoptosis / genetics
  • Biomarkers, Tumor / analysis
  • Blotting, Western
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology*
  • Cell Proliferation / genetics
  • Disease-Free Survival
  • Female
  • Gene Expression Regulation, Neoplastic / genetics*
  • Heterografts
  • Humans
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / biosynthesis*
  • Kaplan-Meier Estimate
  • Liver Neoplasms / genetics
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics*
  • Middle Aged
  • Prognosis
  • Protein Serine-Threonine Kinases / biosynthesis*
  • Real-Time Polymerase Chain Reaction
  • Transfection

Substances

  • Biomarkers, Tumor
  • Intracellular Signaling Peptides and Proteins
  • MIRN194 microRNA, human
  • MicroRNAs
  • MAP4K4 protein, human
  • Protein Serine-Threonine Kinases