Carcinogenesis Advance Access published online on August 29, 2003
Carcinogenesis, doi:10.1093/carcin/bgg145
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
* Corresponding author. E-mail: hrmsfst{at}hkucc.hku.hk.
Received 25 April 2003
; revised 27 July 2003
; accepted 4 August 2003
Inhibitors of differentiation and DNA binding-1 (Id-1) has been demonstrated to oppose Ets-mediated activation of p16INK4a. Since p16INK4a protein is inactivated in hepatocellular carcinoma (HCC), we aimed to investigate the role of Id-1 in regulating p16INK4a expression during the development of HCC in HCC patients and direct ectopic Id-1 introduction into the PLC/PRF/5 HCC cell line. Sixty-two HCC samples were recruited for evaluation of Id-1 and proliferating cell nuclear antigen (PCNA) protein expression. The messenger RNA (mRNA) expression of Id-1 and p16INK4a was detected by quantitative reverse transcription-polymerase chain reaction. For in vitro Id-1 transfection, 5 Id-1 transfected clones were isolated and the effect of ectopic Id-1 introduction was investigated by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, flow cytometry, immunostaining, and Western blot. Our results showed that Id-1 was over-expressed in HCC specimens both at mRNA and protein levels. Over-expression of Id-1 protein was correlated with PCNA (r = 0.334, P = 0.033). HCC samples showing low Id-1 protein expression had a lower Id-1 mRNA level (340.2% vs. 1467%, P = 0.039) and higher p16INK4a expression (195% vs -78.6%, P = 0.039) than samples with high Id-1 protein expression. In the PLC/PRF/5 HCC cell line study, ectopic Id-1 expression resulted in proliferation of HCC cells and an increased percentage of S phase cells and PCNA expression. The results showed that over-expression of Id-1 induces cell proliferation in HCC through inactivation of p16INK4a/retinoblastoma pathway. In conclusion, the results provided an insight for the understanding of the role of Id-1 in functional inactivation of p16INK4a in HCC.
CDK4, phosphorylation, helix-loop-helix, PLC/PRF/5, PCNA
Over-expression of Id-1 induces cell proliferation in hepatocellular carcinoma through inactivation of p16INK4a/RB pathway
2 Centre for the Study of Liver Disease and Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong, China
3 Centre for the Study of Liver Disease and Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong, China
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