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Background: Holliday junction recognition protein (HJURP) has been implicated in many cancers including hepatocellular carcinoma (HCC). However, the underlying mechanism by which HJURP promotes HCC cell proliferation remains unclear. Methods: RT-qPCR and immunohistochemistry were used to detect HJURP expression in HCC and adjacent tumor tissues and HCC cell lines. The localization of p21 were determined by immunofluorescence and western blot. Co-immunoprecipitation and western blot were used to validate the p21 stability and signaling pathways affected by HJURP. The effects of HJURP on HCC cell proliferation were assessed both in vivo and in vitro. The ERK1/2 pathway inhibitor U0126 and AKT pathway agonist SC-79 were used to treat HCC cell lines for further mechanistic investigations. Results: HJURP expression was higher in HCC tissues than in para-tumor tissues. Moreover, ectopic HJURP expression facilitated the proliferation of HCC cells, whereas the depletion of HJURP resulted in decreased cell growth in vitro and in vivo. Furthermore, the effects of HJURP silencing were reversed by p21 knockdown. Likewise, p21 overexpression inhibited cell growth ability mediated by HJURP elevation. Mechanistically, HJURP destabilized p21 via the MAPK/ERK1/2 and AKT/GSK3β pathways, which regulated the nucleus-cytoplasm translocation and ubiquitin-mediated degradation of p21. Clinically, high HJURP expression was correlated with unfavorable prognoses in HCC individuals. Conclusions: Our data revealed that HJURP is an oncogene that drives cell cycle progression upstream of p21 in HCC. These findings may provide a potential therapeutic and prognostic target for HCC. [ABSTRACT FROM AUTHOR]