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Aberrance of retinoblastoma protein (RB) signal pathway is known to play an important role in the carcinogenesis of human hepatocellular carcinoma (HCC). p28GANK, originally purified from human 26S proteasome as a non-ATPase subunit, was recently found in HCC and shown to interact with RB. The aim of this study was to investigate the expression profile of p28GANK and its correlation with RB in HCC.The expression of p28GANK was evaluated in 55 surgically resected HCCs by immunohistochemistry (IHC), and the associations were explored between p28GANK level and clinicopathologic features as well as tumor suppressor RB. Western blotting was performed to determine p28GANK expression level in 12 HCCs. Immunofluorescence stainings of p28GANK and RB in U2-OS cells were examined by confocal microscopy.Positive p28GANK cytoplasmic staining was recognized in 55 HCCs. Nuclear positive occurrence of p28GANK in HCCs was more frequent than paracancerous hepatic tissues (P < 0.05). The overexpression probability of p28GANK was inversely associated with Edmonson's grade: overexpression occurred in nine out of 11 (81.8%), 22 out of 35 (62.9%) and two out of nine (22.2%) in I–II, III and IV graded cases, respectively (P = 0.004). Total cellular expression of p28GANK had curvilinear correlation with the nuclear expression of RB (r = 0.475, P = 0.019), while the nuclear expression of p28GANK had not. Western blot analysis showed that up-regulation of p28GANK expression was found in nine out of 12 HCCs compared with paracancerous liver tissues. Exogenously expressed p28GANK colocalized with RB in cytoplasm of U2-OS cells.These results confirm the role of p28GANK as a highly expressed oncoprotein in HCC by in situ examination. Its overexpression correlates with the differentiation status of HCC. The whole cellular p28GANK activation, not nuclear portion only, influences the alteration of RB. Underlying nuclear translocation of p28GANK may contribute to the counteraction against RB through a feed back loop. These data provide new evidence for p28GANK to be used as a promising drug target of a therapeutic agent against HCC.