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  • Title: MiR-222 overexpression confers cell migratory advantages in hepatocellular carcinoma through enhancing AKT signaling.
    Author: Wong QW, Ching AK, Chan AW, Choy KW, To KF, Lai PB, Wong N.
    Journal: Clin Cancer Res; 2010 Feb 01; 16(3):867-75. PubMed ID: 20103675.
    Abstract:
    PURPOSE: This study aims to profile the expressions of 156 microRNAs (miRNA) in hepatocellular carcinoma (HCC) and to characterize the functions of miR-222, the most significantly upregulated candidate identified. EXPERIMENTAL DESIGN: miRNA expression profile in HCC tumors, matching adjacent cirrhotic livers, and cell lines was conducted using quantitative PCR. Common miR-222 upregulations were further validated in a larger cohort of tumors. The functional effects of miR-222 inhibition on HCC cell lines were examined. The downstream modulated pathways and target of miR-222 were investigated by coupling gene expression profiling and pathway analysis, and by in silico prediction, respectively. Luciferase reporter assay was done to confirm target interaction. RESULTS: We identified a 40-miRNA signature that could discriminate tumors from adjacent cirrhotic liver tissue, and further corroborated common miR-222 overexpression in tumors relative to its premalignant counterpart (55.3%; P < 0.0001). Increased miR-222 expression correlated significantly with advanced stage HCC and with the shorter disease-free survival of patients (P < or = 0.01). Inhibition of miR-222 in Hep3B and HKCI-9 significantly retarded cell motility (P < 0.05). Further investigations suggested that AKT signaling was the major pathway influenced by miR-222. A consistent reduction of AKT phosphorylation in Hep3B and HKCI-9 was shown following miR-222 suppression. The protein phosphatase 2A subunit B (PPP2R2A) was predicted as a putative miR-222 target in silico. We found that miR-222 inhibition could augment the tumor protein level and restore luciferase activity in reporter construct containing the PPP2R2A 3' untranslated region (P = 0.0066). CONCLUSIONS: Our study showed that miR-222 overexpression is common in HCC and could confer metastatic potentials in HCC cells, possibly through activating AKT signaling.
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