Basic–liver, pancreas, and biliary tractMicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer
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Cell Lines, Cultures, and HCC Tumor Tissues
Malignant hepatocyte cell lines were obtained from the American Type Culture Collection (Manassas, VA) and cultured as recommended by the supplier. Normal human hepatocytes were obtained from Sciencell (San Diego, CA). For miRNA profiling, total RNA from normal human liver tissue and from HCC was obtained from BioChain Institute, Inc. (Hayward, CA). For miR-21 expression, RNA was obtained from tumor samples with histologic evidence of HCC, and nontumoral samples from adjacent liver without
Expression of miRNAs in HCC
We first isolated and compared the miRNA expression profile from normal liver and HCC tumor tissue (Figure 1). Eight microarray hybridization studies were performed on 3 different pairs of tumor and normal human liver–derived RNA. The miRNAs that are overexpressed differentially in HCC included miR-21, miR-34a, miR-221, miR-213, miR-376a, miR-222, miR-373, miR-210, and miR-294 (Table 1). Of the miRNAs that had decreased expression, the greatest changes were noted for miR-92-1 and miR-199a-1. A
Discussion
Although a role for miRNAs in cancer has been proposed, the molecular mechanisms by which miRNA can modulate tumor growth or metastases are unknown. We show that miR-21 expression is increased in malignant hepatocytes, and in human HCC compared with matching nontumoral tissue. Moreover, we show that miR-21 promotes cell invasion, migration, and growth via repression of PTEN expression and downstream effects involving the phosphorylation of FAK and Akt, and the expression of MMP-2 and MMP-9. The
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Supported by the Scott and White Hospital Foundation, and by grants DK069370 and CA122694 from the National Institutes of Health.