TGF-beta1-induced cell growth arrest and partial differentiation is related to the suppression of Id1 in human hepatoma cells.
Transforming growth factor beta 1 (TGF-beta1) 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-beta1 in four HCC cell lines, and studied the changes in cell proliferation, cell cycle and differentiation. The four HCC cell lines expressed Id1, TGF-beta1 and their receptors at various levels. TGF-beta1 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-beta1-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-beta1 dose-dependently suppressed Id1 expression in HuH7 cells; 1 ng/ml TGF-beta1 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-beta1 growth inhibitory effect, lacked TGF-beta receptors and Id1 expression was not altered. In PLC/PRF/5 cells, Id1 augmentation was not observed in response to TGF-beta1, indicating that TGF-beta1-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-beta1 may be important in TGF-beta1-induced growth inhibition and partial differentiation.
Damdinsuren
Bazarragchaa
B
Department of Surgery, Graduate School of Medicine, Osaka University, E2, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Nagano
Hiroaki
H
Kondo
Motoi
M
Natsag
Javzandulam
J
Hanada
Hiroyuki
H
Nakamura
Masato
M
Wada
Hiroshi
H
Kato
Hitoshi
H
Marubashi
Shigeru
S
Miyamoto
Atsushi
A
Takeda
Yutaka
Y
Umeshita
Koji
K
Dono
Keizo
K
Monden
Morito
M
D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D016212:Transforming Growth Factor beta