, Volume 324, Issue 3, pp 385-394
Date: 01 Mar 2006

Involvement of the tyrosine phosphatase early gene of liver regeneration (PRL–1) in cell cycle and in liver regeneration and fibrosis effect of halofuginone

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Abstract

Tyrosine phosphatase PRL–1 is one of the immediate-early genes up-regulated during liver regeneration and is apparently involved in cell proliferation. Previously, we have demonstrated that halofuginone, an inhibitor of collagen type I synthesis, prevents liver fibrosis and improves cirrhotic liver regeneration. In this study, we evaluated the effect of halofuginone on PRL–1 expression, its cellular localization in vitro and during liver regeneration, and fibrosis progression in vivo. In culture, halofuginone increased PRL–1 expression in primary rat hepatocytes and in hepatocellular carcinoma (HCC) cell lines, the former being more sensitive to halofuginone. The halofuginone-dependent increase in PRL–1 gene expression was correlated with an increase in the transcription factor early growth response–1 (Egr–1) and inversely correlated with the inhibition of cell proliferation. Halofuginone arrested HepG2 and Huh7 cell lines at the G1 phase, whereas Hep3B cells were arrested at G2/M, probably because of a reduction in the synthesis of cyclins D1 and B1 in all HCC cells and increased cyclin A in Hep3B cells. Halofuginone also affected the PRL–1 sub-cellular localization that was cell-cycle-dependent. In addition, halofuginone augmented PRL–1 expression in the remnant liver after partial hepatectomy and in chemically induced fibrosis in rats; this was accompanied by increased expression of insulin-like growth factor binding protein 1 (IGFBP–1), another immediate-early gene of regeneration. The regulation of the expression of the early genes of regeneration such as PRL–1 and IGFBP–1 is thus part of the mode of action of halofuginone and results in the prevention of liver fibrosis and improved cirrhotic liver regeneration.

This study was supported by the Israel Science Foundation (ISF) 537/01 and is a contribution from the Agricultural Research Organization, Volcani Center, Bet Dagan, Israel (no. 462–04, 2004 series).