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Purpose CD276 protein expression and vasculogenic mimicry (VM) formation are associated with the poor prognosis of hepatocellular carcinoma (HCC) patients. Although both the effects of CD276 and VM formation involve the activation of matrix metalloproteinases, and their relationship has not yet been explored. The following study investigated the effect of CD276 expression on VM formation and the potential mechanisms. Materials and Methods CD276 expression and VM were examined in commercial tissue microarrays by immunohistochemistry and CD31/PAS double staining. Tumor cell proliferation, invasion, migration and, tube formation were detected in vitro after transfecting HCC cell lines with an shRNA lentiviral vector against CD276. The expression of MMP14, MMP2, VE-cadherin, E-cadherin, and vimentin and MMPs activation was detected by Western blot, immunofluorescence and gelatin zymography assay. In addition, an orthotopic xenograft model of HCC cells was established in vivo, after which VM was detected, along with its marker molecules. Results CD276 expression was associated with VM and poor prognosis in HCC patients. RNA interference of CD276 reduced tumor cell proliferation, invasion, migration, and VM formation in vitro and in vivo. Furthermore, CD276 knockdown up-regulated the expression of E-cadherin but inhibited the phosphorylation of AKT, the expression of MMP14, MMP2, VE-cadherin, vimentin and the activation of MMP2 and MMP9 in HCC cell lines. Conclusion CD276 may promote VM formation by activating the PI3K/AKT/MMPs pathway and inducing the EMT process in HCC. CD276 may serve as a promising candidate for the anti-VM treatment of HCC.