Methylation status of p14ARF, p15INK4b, and p16INK4a genes in human hepatocellular carcinoma

Authors

  • Kenichi Fukai,

    1. Departments of 1Medicine and Clinical Oncology, 2General Surgery3Academic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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  • 1 Osamu Yokosuka,

    1. Departments of 1Medicine and Clinical Oncology, 2General Surgery3Academic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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  • 1 Fumio Imazeki,

    1. Departments of 1Medicine and Clinical Oncology, 2General Surgery3Academic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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  • 1 Motohisa Tada,

    1. Departments of 1Medicine and Clinical Oncology, 2General Surgery3Academic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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  • 1 Rintaro Mikata,

    1. Departments of 1Medicine and Clinical Oncology, 2General Surgery3Academic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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  • 1 Masaru Miyazaki,

    1. Departments of 1Medicine and Clinical Oncology, 2General Surgery3Academic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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  • 2 Takenori Ochiai,

    1. Departments of 1Medicine and Clinical Oncology, 2General Surgery3Academic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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  • and 3 Hiromitsu Saisho 1

    1. Departments of 1Medicine and Clinical Oncology, 2General Surgery3Academic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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Osamu Yokosuka, MD, Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-0856, Japan.
Tel: +81-43-222-7171 (Ext. 5244)
Fax: +81-43-226-2088
e-mail: yokosuka@med.m.chiba-u.ac.jp

Abstract

Abstract: Background: The INK4 locus consisting of three genes involved in the regulation of cell cycle, p16INK4a, p15INK4b, and p14ARF is often disrupted in human neoplasms.

Methods: We analyzed the promoter methylation of each gene by methylation-specific PCR in hepatocellular carcinoma (HCC).

Results: The methylation of p16INK4a, p15INK4b, and p14ARF was found to occur in 27 (69.2%), seven (17.9%), and none out of 39 HCC tumors, respectively. Regarding corresponding nontumorous liver tissues, the promoter regions of p16INK4a, p15INK4b, and p14ARF were methylated in three (17.6%), three (17.6%), and none out of 17 samples, respectively. Analysis of mRNA expression revealed that loss of p16INK4a expression was frequently observed in HCC. In contrast, transcripts of p14ARF and p15INK4b were detected in 16 (88.9%) and 16 (88.9%) of 18 tumors, respectively.

Conclusions: The frequent loss of transcription of p16INK4a with promoter methylation not only in the advanced but also in the early stages of HCC suggests that the epigenetic alteration of p16INK4a promoter is likely to be involved in hepatocarcinogenesis. Together with the result of RT-PCR analysis, the role of aberrant methylation of p14ARF or p15INK4a promoter in hepatocarcinogenesis is thought to be limited.

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