Abstract
β-arrestins, including β-arrestin1 and β-arrestin2, are multifunctional adaptor proteins. β-arrestins have recently been found to play new roles in regulating intracellular signalling networks associated with malignant cell functions. Altered β-arrestin expression has been reported in many cancers, but its role in hepatocellular carcinoma (HCC) is not clear. We therefore examined the roles of β-arrestins in HCC using an animal model of progressive HCC, HCC patient samples and HCC cell lines with stepwise metastatic potential. We demonstrated that β-arrestin2 level, but not β-arrestin1 level, decreased in conjunction with liver tumourigenesis in a mouse diethylnitrosamine-induced liver tumour model. Furthermore, β-arrestin2 expression was reduced in HCC tissues compared with noncancerous tissues in HCC patients. β-arrestin2 down-regulation in HCC was significantly associated with poor patient prognoses and aggressive pathologic features. In addition, our in vitro study showed that β-arrestin2 overexpression significantly reduced cell migration and invasion in cultured HCC cells. Furthermore, β-arrestin2 overexpression up-regulated E-cadherin expression and inhibited vimentin expression and Akt activation. These results suggest that β-arrestin2 down-regulation increases HCC cell migration and invasion ability. Low β-arrestin2 expression may be indicative of a poor prognosis or early cancer recurrence in patients who have undergone surgery for HCC.
Highlights
Β-arrestins can transduce multiple signals in cells, little is known about their participation in HCC progression
We found that β-arrestin[2] is expressed in low levels in HCC tissues compared with peritumoural tissues, and that its low expression is strongly associated with aggressive pathologic features and is predictive of a poor prognosis in HCC patients after surgery
The black line was used to mark the ranges of the scratches. (c) Transwell Matrigel invasion assays showed that the number of invasive cells in the β-arrestin[2] small interfering RNA (siRNA)-treated group increased significantly compared with the number of invasive cells in the control group. **P < 0.01 compared with the control group
Summary
Β-arrestins can transduce multiple signals in cells, little is known about their participation in HCC progression. This study was designed to investigate the role of β-arrestins in HCC and HCC cell invasion. The data presented indicate that β-arrestin[2] expression gradually decreases with increasing HCC cell line metastatic potential, and that β-arrestin[2] overexpression inhibits HCC cell metastasis and invasion, reduces Akt activation, increases E-cadherin expression, and decreases vimentin expression. These findings suggest that β-arrestin[2] acts by down-regulating the Akt pathway to inhibit HCC cell metastasis and invasion. These findings suggest that β-arrestin[2] acts by down-regulating the Akt pathway to inhibit HCC cell metastasis and invasion. β-arrestin[2] may has potential as a prognostic and treatment marker in HCC
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