MiR-222 Overexpression Confers Cell Migratory Advantages in Hepatocellular Carcinoma through Enhancing AKT Signaling
| Autor: | Nathalie Wong, Anthony Wh Chan, Kwong Wai Choy, Queenie W-L Wong, Paul B.S. Lai, Arthur K-K Ching, Ka Fai To |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Liver Cirrhosis
Cancer Research Pathology medicine.medical_specialty Carcinoma Hepatocellular Cell Biology Cell Movement RNA interference microRNA medicine Humans Gene silencing Protein kinase B Liver Neoplasms Cancer medicine.disease Up-Regulation Gene expression profiling MicroRNAs medicine.anatomical_structure Oncology Hepatocellular carcinoma Disease Progression Cancer research Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Clinical Cancer Research. 16:867-875 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-09-1840 |
| Popis: | 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 ≤ 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. Clin Cancer Res; 16(3); 867–75 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|