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Objective: PHLDA2 has been reported as a proapoptotic factor in osteosarcoma.To determine the regulatory mechanisms of PHLDA2, we focused on microRNAs (miRNAs) known to key regulators of mRNAs, and defined the relationship between miRNA expression and the sensitivity to radiotherapy in osteosarcoma.Methods:Using bioinformatic analyses and luciferase reported assay, the miRNA targeted PHLDA2 was characterized.Then, the manipulation of rniRNA was transfected by the mimic or antisense oligonucleotides,and the effect of miRNA on proliferation, apoptosis and radiation sensitivity was assessed.The expression of miRNA and PHLDA2 then measured in 30 samples from osteosarcoma patients which never received with any chemotherapy or radiotherapy.Results: miR-214 negatively regulated the expression of PHLDA2, via targeting its 3UTR, thereby increased proliferation and inhibited irradiation-induced apoptosis.Vice verse, knockdown of miR-214 enhanced apoptosis in induction of irradiation in vitro and in vivo assays.The biological effect of miR-214 on osteosarcoma was largely mediated by phosphatidylinositol-3-kinase/Akt signaling, in that inhibition of Akt activation reversed its impact on apoptosis induced by irradiation.miR-214 was overexpressed in majority of osteosarcoma tissues relative to paired nontumor bone tissues.The increased miR-214 was positively associated with lung matastasis and inversely correlated with PHLDA2.Conclusions: Upregulation of miR-214 is a common event, and strongly affected the radiosensitivity of ostoesarcoma through targeting the P HLDA2/Akt pathway.These findings suggesting that knockdown miR-214 may represent a new approach to sensitize osteosarcoma to irradiation.