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Study on the role of DNA methyltransferases in regulation of the expression of genes associated with the control of cell cycle

Research Project

Project/Area Number 14571880
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Surgical dentistry
Research InstitutionChiba University

Principal Investigator

BUKAWA Hiroki  Chiba University, University Hospital, Lecturer, 医学部附属病院, 講師 (80173558)

Co-Investigator(Kenkyū-buntansha) TANZAWA Hideki  Chiba University, Graduate School of Medicine, Professor, 大学院・医学研究院, 教授 (50236775)
UZAWA Katsuhiro  Chiba University, Graduate School of Medicine, Associate Professor, 大学院・医学研究院, 助教授 (30302558)
SHIIBA Masashi  Chiba University, Graduate School of Medicine, Assistant, 大学院・医学研究院, 助手 (20301096)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥3,000,000 (Direct Cost: ¥3,000,000)
KeywordsDNA methyltransferase / oral squamous cell carcinoma / DNA methylation / APC gene / p16 gene / FEZ1 gene / KAI1 gene / survivin / 口腔扁平上皮癌 / DNA methyltransferase / APC遺伝子 / FEZ1遺伝子 / p73遺伝子
Research Abstract

To estimate the involvement of methylation in the down-regulation of the genes, APC, p16, FEZ1, KAI1, and survivine, wehich were associated with the regulation of cell cycle, we examined the expression revels of them and methyltransferases, DNMT1, DNMT3A, and DNMT3B, which were believed to be associated with carcinogenesis, in 8 cell lines, SAS, HSC-2, HSC-3, HSC-4, Ca9-22, OK-92, HO-1-u-1, and HO-1-N-1, which were derived from oral carcinoma, and clinical tissue samples of oral cancer. Additionally, restoration of the gene expression by 5-Aza-C, one of the demethylation agents, was examined. The hyper methylation of CDKN2A/p16 gene was detected in 24 (48.0%) of 50 oral squamous cell carcinoma cases (OSCC) and the restoration by 5-Aza-C was found in 6 (75.0%) of 8 cell lines. The down expression of APCgene was detected in 15 (30.0%) of 50cases, and hypermethylation of CPG island was found 12 (24.0%) of the all cases. Suppressed expression and hypermethylation of FEZ1gene was detected i … More n 11 (35.5%) and in 8 (25.8%) of 31 case, respectively. Out of the 31 cases, hypermethylation was detected and restoration of the gene expression by 5-Aza-C was found in all of the 8 cell lines. Silence or suppressed expression of KAI1 gene was detected in 84 of 101 OSCC cases. However, neither hypermethylation of CPG island of the promoter region nor restoration of the gene expression by 5-Aza-C was not found. The over-expression of surviving gene was detected in 58% of OSCC cases and in 37% of precancerous lesion, leukoplakia. On the other hand, the expression of surviving gene was not detected by RT-PCRin all of the 9 normal oral epitherium tissues and DNA methylation was confirmed by methylation specific PCR in 4 of the 9 normal specimens and the gene expression was restored by 5-Aza-Ctreatment in 2 of 8 cell lines. The over-expression of DNA methyltransferase, DNMTs ; DNMT1, DNMT3A, and DNMT3B, which were believed to be associated with carcinogenesis, were high frequently detected in OSCC. The rates of the expression of DNMTI, DNMT3A, and DNMT3B in OSCC were 72%, 56%, and 64%, respectively. There was no significant correlation between the expression levels and the situations of hypermethylation of the tumor suppressor and oncogenes examined and the expression levels of methyltransferases. Our data suggest that hypermethylation of the gene may be one of the major mechanisms for inactivation of the genes in oral carcinogenesis and that besides methyltransferases, some transcription factors involved in the suppression of gene expression might play an important roles in ora oncogenesis. Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (13 results)

All Other

All Publications (13 results)

  • [Publications] Tanaka C, Uzawa K, Shibahara T, Yokoe H, Noma H, Tanzawa H.: "Expression of an inhibitor of apoptosis, surviving, in oral carcinogenesis."J Dent Res. 82. 607-611 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ono K, Uzawa K, Nakatsuru M, Shiiba M, Mochida V, Tada A, Bukawa H, Miyakawa A, Yokoe H, Tanzawa H.: "Down-regulation of FEZ1/LZTS1 gene with frequent loss of heterozygosity in oral squamous cell carcinomas."Int J Oncol. 23. 297-302 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yakushiji T, Uzawa K, Shibahara T, Noma H, Tanzawa H.: "Over-expression of DNA methyltransferases and CDKN2A gene methylation status in squamous cell carcinoma of the oral cavity."Int J Oncol. 22. 1201-1207 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Uzawa K, Ono K, Suzuki H, Tanaka C, Yakushiji T, Yamamoto N, Yokoe H, Tanzawa H.: "High prevalence of decreased expression of KAI1 metastasis suppressor in human oral carcinogenesis."Clinical Cancer Research. 8. 828-835 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tanaka C, Uzawa K, Shibahara T, Yokoe H, Noma H, Tanzawa H.: "Expression of an inhibitor of apoptosis, surviving, in oral carcinogenesis."J Dent Res. 82. 607-611 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Uzawa K, Ono K, Suzuki H, Tanaka C, Yakushiji T, Yamamoto N, Yokoe H, Tanzawa. H.: "High prevalence of decreased expression of KAI1 metastasis suppressor in human oral carcinogenesis."Clinical Cancer Research. 8. 828-835 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ono K, Uzawa K, Nakatsuru M, Shiiba M, Mochida Y, Tada A, Bukawa H, Miyakawa A, Yokoe H, Tanzawa H.: "Down-regulation of FEZ1/LZTS1 gene with frequent loss of heterozygosity in oral squamous cell carcinomas."Int J Oncol. 23. 297-302 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yakushiji T, Uzawa K, Shibahara T, Noma H, Tanzawa H.: "Over-expression of DNA methyltransferases and CDKN2A gene methylation status in squamous cell carcinoma of the oral cavity."Int J Oncol. 22. 1201-1207 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tanaka C, Uzawa K, Shibahara T, Yokoe H, Noma H, Tanzawa H.: "Expression of an inhibitor of apoptosis, surviving, in oral carcinogenesis."J Dent Res. 82. 607-611 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ono K, Uzawa K, Nakatsuru M, Shiiba M, Mochiba Y, Tada A, Bukawa H, Miyakawa A, Yokoe H, Tanzawa H.: "Down-rogulation of FEZ1/LZTS1 gene with frequent loss of heterozygosity in oral squamous cell carcinomas."Int J Oncol. 23. 297-302 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yakushiji T, Uzawa K, Shibahara T, Noma H, Tanzawa H.: "Over-expression of DNA methyltransferases and CDKN2A gene methylation status in squamous cell carcinoma of the oral cavity."Int J Oncol. 22. 1201-1207 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Uzawa K, Ono K, Suzuki H, Tanaka C, Yakushiji T, Yamamoto N, Yokoe H, Tanzawa H.: "High prevalence of decreased expression of KAI1 metastasis suppressor in human oral carcinogenesis."Clinical Cancer Research. 8. 828-835 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Uzawa K, Ono K, Suzuki H, Yokoe H, Tanzawa H.: "High prevalence of decreased expression of KAI1 metastasis suppressor in human oral carcinogenesis"Clinical Cancer Research. 8. 828-835 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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