Journal Article

Over-expression of Id-1 induces cell proliferation in hepatocellular carcinoma through inactivation of p16<sup>INK4a</sup>/RB pathway

Terence Kin-Wah Lee, Kwan Man, Ming-Tat Ling, Xiang-Hong Wang, Yong-Chuan Wong, Chung-Mau Lo, Ronnie Tung-Ping Poon, Irene Oi-Lin Ng and Sheung-Tat Fan

in Carcinogenesis

Volume 24, issue 11, pages 1729-1736
Published in print November 2003 | ISSN: 0143-3334
Published online November 2003 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgg145
Over-expression of Id-1 induces cell proliferation in hepatocellular carcinoma through inactivation of p16INK4a/RB pathway

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Inhibitors of differentiation and DNA binding-1 (Id-1) have been demonstrated to oppose Ets-mediated activation of p16INK4a. As 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, five 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 versus 1467%, P = 0.039) and higher p16INK4a expression (195 versus −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.

Keywords: FBS, fetal bovine serum; HCC, hepatocellular carcinoma; Id, inhibitors of differentiation and DNA binding; mRNA, messenger RNA; MTT, 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; PCNA, proliferating cell nuclear antigen; PCR, polymerase chain reaction; RB, retinoblastoma; RT–PCR, reverse transcription-polymerase chain reaction

Journal Article.  4538 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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