TGF-β1-induced cell growth arrest and partial differentiation is related to the suppression of Id1 in human hepatoma cells

Abstract

Abstract. Transforming growth factor beta 1 (TGF-ß1) is a proposed regulator of Ids (inhibitors of DNA binding/differentiation) gene expression in epithelial cells. We previously reported that Id proteins are variously expressed in human hepatocellular carcinomas (HCC). However, the mechanism of regulation of Ids in HCC remains obscure. Here, we examined the relationship between Id1 and TGF-ß1 in four HCC cell lines, and studied the changes in cell proliferation, cell cycle and differentiation. The four HCC cell lines expressed Id1, TGF-ß1 and their receptors at various levels. TGF-ß1 strongly inhibited the growth of HuH7 cells, while the growth inhibition was moderate in PLC/PRF/5, and was not observed in HLE and HLF cell lines. TGF-ß1-induced growth inhibition in HuH7 cells was associated with cell accumulation in the G1 phase and partial induction of differentiation (with reduction of AFP and AFP-L3). Induction by TGF-ß1 dose-dependently suppressed Id1 expression in HuH7 cells; 1 ng/ml TGF-ß1 inhibited Id1 by 84.0 and 78.6% that of the untreated control at transcriptional and protein levels, respectively. HLE and HLF cells, which did not exhibit a TGF-ß1 growth inhibitory effect, lacked TGF-ß receptors and Id1 expression was not altered. In PLC/PRF/ 5 cells, Id1 augmentation was not observed in response to TGF-ß1, indicating that TGF-ß1-induced growth inhibition was not related to Id1 in this cell line. Our results suggest that, in some HCC cells, the pathway of suppression of Id1 by TGF-ß1 may be important in TGF-ß1-induced growth inhibition and partial differentiation.

Reactive Oxygen Species Act as Signaling Molecules in Liver Carcinogenesis

“…We could demonstrate that IFN -2b or TGF 1 stimulations not only decreased cellular proliferation but also increased apoptotic cell death [142]. The apoptotic and anti-proliferative effects of both cytokines separately have already been reported in HepG2 and Huh7 [143][144][145]. More interestingly, we demonstrated that the combined treatment increased these effects.…”

PKN Activation via Transforming Growth Factor-β1 (TGF-β1) Receptor Signaling Delays G2/M Phase Transition in Vascular Smooth Muscle Cells

“…With respect to studies concerning the G 1 /S transition, a role for TGF-β1 receptor signaling in a various cell types has been well documented. [54][55][56][57] These studies have established that a transitory arrest in cell proliferation occurs during G 1 /S phase transition. This delay appears to be mediated by the induced expression of cyclin-dependent kinase inhibitors (CKIs) such as p15 ink4b (p15), p21 cip1 (p21) and p27 kip1 (p27), 58 and by the down-regulation of a critical G 1 /S phosphatase Cdc25A.…”

Tubular Epithelial Cell Dedifferentiation Is Driven by the Helix-Loop-Helix Transcriptional Inhibitor Id1

“…The reason behind the discrepancy between the kinetics of Id1 mRNA and protein induction remains unknown at this stage, but it could be related to an altered stability of Id1 protein. It should be noted that several reports demonstrate a repression of Id1 expression by TGF-␤1 in different cells (33,34), suggesting that the response of Id1 expression to TGF-␤1 is dictated by the particular contents of the cells. Consistent with this notion, recent studies also indicate that TGF-␤1 induces Id1 expression in rat hepatic stellate cells and human fetal lung fibroblasts (35,36).…”