To study the effect of the two arms of miR-590, miR-590-5p and miR-590-3p, on hepatoma cell proliferation and their roles in tumor development.We analyzed and verified the expression pattern of miR-590 in liver cancer specimens and cell lines by miRNA microarrays and QPCR. MiR-590 mimic or inhibitor was transfected into normal liver cells or liver cancer cells via liposome, and the changes in cell proliferation and survival were determined by MTT assay and soft agar colony formation assay. The target genes of miR-590-5p and miR-590-3p were predicated with Targetscan and validated by luciferase reporter system and Western blotting.The expressions of miR-590-5p and miR-590-3ps were up-regulated in 3 hepatocellular carcinoma (HCC) tissues and their synchronization was significantly up-regulated in 8 out of 10 HCC tissues as compared with the adjacent tissues. QPCR further showed that miR-590-5p/3p was up-regulated in 3 HCC cell lines (HepG2, Hep3B, and Huh7) in comparison with the normal liver cell line L-O2. L-O2 cells over-expressing miR-590-5p and miR-590-3p exhibited significantly increased proliferation (P<0.05), while down-regulation of miR-590-5p and miR-590-3p caused significantly suppressed proliferation in HepG2, Hep3B, and Huh7 cells. Targetscan predicted PDCD4 and PTEN as the potential target genes of miR-590-5p and miR-590-3p, which was verified by luciferase reporter system and Western blotting. miR-590-3p was found to activate PI3K-AKT signaling pathway by down-regulating PTEN to promote AKT1-S473 phosphorylation.MiR-590 is an important tumorigenic factor for HCC, and its two arms can both promote tumorigenesis by regulating the expression of their target tumor suppressor gene, PDCD4 and PTEN, to promote HCC cell proliferation and survival and activate the core tumor signal pathway PI3K-AKT.