MicroRNA-197 Promotes Metastasis of Hepatocellular Carcinoma by Activating Wnt/ß-Catenin Signaling.

ABSTRACT

BACKGROUND/AIMS: MicroRNA-197 (miR-197) has been shown to play roles in epithelialmesenchymal transition (EMT) and metastasis. The Wnt/ß-catenin pathway is associated with EMT, but whether miR-197 regulatesWnt/ß-catenin remains unclear. This study was to demonstrate the role of miR-197 on the Wnt/ß-catenin pathway in hepatocellular carcinoma (HCC). METHODS: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-197 in 105 HCC specimens and 15 HCC cell lines. We tested the predicted target gene of miR-197 using a genetic report system. The role of miR-197 in HCC cell invasion and migration (wound healingand cell invasion and migrationby Transwell assays) and in an HCC xenograft modelwas analyzed. RESULTS: Using a miRNA microarray analysis of HCC specimens and compared with non-metastatic HCC, miR-197 was identified as one of the most upregulated miRNAs in metastatic HCC. miR-197 expression was positively associated with the invasiveness of HCC cell lines. Metastatic HCC cells with high miR-197 expression had Wnt/ß-catenin signaling activation. High levels of miR-197 expression also promoted EMT and invasionHCC cells in vitro and in vivo. miR-197 directly targeted Axin-2, Naked cuticle 1 (NKD1), and Dickkopf-related protein 2 (DKK2), leading to inhibition of Wnt/ß-catenin signaling. High miR-197 expression was found in HCC specimens from patients with portal vein metastasis;high miR-197 expression correlated to the expression of Axin2, NKD1, and DKK2. CONCLUSION: miR-197 promotes HCC invasion and metastasis by activating Wnt/ß-catenin signaling. miR-197 could possibly be used as a prognostic marker and therapeutic target for HCC.