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MicroRNAs (miRNAs) serve as major regulators during the tumorigenesis and tumor development of hepatocellular carcinoma (HCC). In addition, miRNAs may serve as new promising biomarkers for the diagnosis and prognosis and as effective therapeutic targets for patients with this malignancy. Therefore, understanding the association between miRNAs and HCC may be beneficial to discover novel therapeutic approaches towards diagnosis and treatments. Results of this study showed that miRNA-337 (miR-337) was markedly downregulated in HCC tissues and cell lines. Decreased miR-337 expression was significantly associated with the TNM stage and lymph node metastasis of HCC. Ectopic expression of miR-337 prohibited the proliferation, colony formation, migration, and invasion of HCC cells. It also promoted the apoptosis in vitro and reduced the tumor growth in vivo of these cells. High-mobility group AT-hook 2 (HMGA2) was identified as a direct target gene of miR-337 in HCC through a series of experiments. HMGA2 was significantly overexpressed in HCC tissues and negatively correlated with miR-337 expression. Moreover, the functions of HMGA2 inhibition were similar to those induced by miR-337 in HCC. Restored HMGA2 expression rescued the tumor-suppressive roles of miR-337 overexpression in HCC. Furthermore, miR-337 overexpression inhibited the activation of PI3K/AKT and Wnt/β-catenin signaling pathways in HCC both in vitro and in vivo. This study demonstrated that miR-337 may play tumor-suppressing roles in HCC, at least partly, via directly targeting HMGA2 and inhibiting the PI3K/AKT and Wnt/β-catenin signaling pathways. Therefore, miR-337 may be a novel and effective target for the therapeutic treatment of patients with HCC., Competing Interests: None.