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Aims: β-arrestins, including β-arrestinl and β-arrestin2, are multifunctional adaptor proteins.Recently, some new roles of β-arrestins in regulating intracellular signaling networks have been discovered, which regulate malignant cell functions.Altered expression levels of β-arrestins have been reported in many cancers, but its role in hepatocellular carcinoma (HCC) is not clear.Methods: Expression levels of β-arrestinl and β-arrestin2 in diethylnitrosamine (DEN) -induced liver tumor model and clinical samples were examined by Western blot and immunohistochemistry.In vitro, the effects of β-arrestin2 depletion or overexpression on the migration and invasion of HCC cells were observed.Results: β-arrestin2 protein levels in mice liver tissues decreased significantly with liver tumorigenesis, but not β-arrestin1.Further, β-arrestin2 expression was reduced in HCC tissues compared with noncancerous liver tissues in HCC patients.And down-regulation of β-arrestin2 in HCC was associated significantly with poor prognosis of patients and aggressive pathologic features including advanced tumor stages, presence of metastasis, and poorer tumor cellular differentiation.In addition, in vitro study showed that β-arrestin2 was down-regulated in highly metastatic HCC cell lines.In cultured HCC cells, block the expression of β-arrestin2 promoted cell migration and invasion.In contrast, β-arrestin2 overexpression significantly reduced cell migration and invasion.Furthermore, overexpression of β-arrestin2 up-regulated N-cadherin and inhibited the activation of Akt.Conclusions: Down-regulation of β-arrestin2 increased the migration and invasion abilities of HCC cells.Low expression of β-arrestin2 might be used to indicate poor prognosis or early recurrence of cancer in patients who have had surgery for HCC.