Effects of DNA hypermethylation on the oral mucosal diseases

• Project/Area Number: 18390535
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Gifu University
• Principal Investigator: SHIBATA Toshiyuki Gifu University, 大学院・医学系研究科, 教授 (50226172)
• Co-Investigator(Kenkyū-buntansha): YAMASHITA Tomomi 岐阜大学, 医学部附属病院, 講師 (80345793) ; TOIDA Makoto 岐阜大学, 大学院・医学系研究科, 准教授 (90313890) ; KATO Keizou 岐阜大学, 医学部附属病院, 助教 (40397336) ; HARA Akira 岐阜大学, 大学院・医学系研究科, 教授 (10242728) ; 森 秀樹 岐阜大学, 大学院・医学系研究科, 教授 (70021433)
• Project Period (FY): 2006 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥16,200,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,000,000); Fiscal Year 2009: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2008: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2007: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2006: ¥3,200,000 (Direct Cost: ¥3,200,000)
• Keywords: oral cancer / methylation / hypermethylation / carcinogenesis

Research Abstract

本研究は口腔粘膜病変におけるDNAメチル化異常を解析し口腔粘膜病変におけるepigeneticな変化の関与を明らかとするために行った。口腔がん・白板症のp16、MGMT遺伝子のメチル化異常を検索した所、口腔がんではメチル化異常が高い頻度で検出され、周囲健常部分においても約50%の高い頻度で検出された。同様の現象は白板症でも見出された。また、末梢血においてもメチル化異常が検出され腫瘍マーカーとしての意義も見出された。さらに、アルコール・喫煙習慣によっても異常の生じる事が示された(加齢は関係なし)。RECK遺伝子のメチル化制御と浸潤能の変化を検討した所、脱メチル化剤であるDAC,EGCG処理にて制御され、浸潤能の抑制も得られた。また、RECKメチル化異常が予後因子となることも臨床結果より示された。以上より、口腔粘膜病変に遺伝子メチル化異常が深く関与していると考えられた。

Research Products

• [Journal Article] Aberrant promoter hypermethylation of the CHFR gene in oral squamous cell carcinomas. (2009)
  • Author(s): Baba S, Hara A, Kato K, Long NK, Hatano Y, Kimura M, Okano Y, Yamada Y, Shibata T.
  • Journal Title: Oncol Rep. 22(5) Pages: 1173-9
  • NAID: 120006340800
  • Peer Reviewed
• [Journal Article] Global DNA hypermethylation suppresses squamous carnogenesis in the tongue and esophagus. (2009)
  • Author(s): Baba S, Yamada Y, Hatano Y, Miyazaki Y, Mori H, Shibata T, Hara A
  • Journal Title: Cancer Sci. 100(7) Pages: 1186-91
  • Peer Reviewed
• [Journal Article] Aberrant Promoter hypermethylation of the CHFR gene in oralsquamous cell carcinomas. (2009)
  • Author(s): Baba S, Hara A, Kato K, Long NK, Hatano Y, Kimura M, Okano Y, Yamada Y, Shibata T.
  • Journal Title: Oncol Rep. 22 Pages: 1173-1179
  • Peer Reviewed
• [Journal Article] Global DNA hypermethylation suppresses squamous carogenesis in the tongue and esophagus. (2009)
  • Author(s): Baba S, Yamada Y, Hatano Y, Miyazaki Y, Mori H, Shibata T, Hara A.
  • Journal Title: Cancer Sci. 100 Pages: 1186-1191
  • Peer Reviewed
• [Journal Article] Effects of green tea polyphenol on methylation status of RECK gene and cancer cell invasion in oral squamous cell carcinoma cells. (2008)
  • Author(s): Kato K, Long NK, Makita H, Toida M, Yamashita T, Hatakeyama D, Hara A, Mori H, Shibata T
  • Journal Title: Br J Cancer. 99(4) Pages: 647-54
  • Peer Reviewed
• [Journal Article] The effect of hypoxic microenvironment on matrix metalloproteinase expression in xenografts of human oral squamous cell carcinoma. (2008)
  • Author(s): Miyazaki Y, Hara A, Oyama T, Yamada Y, Mori H, Shibata T
  • Journal Title: Int J Oncol. 32(1) Pages: 145-51
  • Peer Reviewed
• [Journal Article] Hypermethylation of the RECK gene predicts poor prognosis in oral squamous cell carcinomas (2008)
  • Author(s): NK Long, K Kato, T Yamashita, H Makita, M Toida, D Hatakeyama, A Hara, H Mori, T Shibata
  • Journal Title: Oral Oncology (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] High frequency of hypermethylation of p14, p15 and p16 in oral pre-cancerous lesions associated with betel-quid chewing in Sri Lanka. (2008)
  • Author(s): M Takeshima, Saitoh M, Kusano K, Nagayasu H, Kurashige Y, Malsantha M, Arakawa T, Takuma T, Chiba I, Shibata T, YAbiko Y.
  • Journal Title: J Oral Pathology and Medicine (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Effects of green tea polyphenol on methylation status of RECK gene and cancer cell invasion in oral squamous cell carcinoma cells (2008)
  • Author(s): Kato, K, Long, NK, Makita, H, Toida, M, Yamashita, T, Hatakeyama, D, Hara, A, Mori, H, Shibata, T.
  • Journal Title: Br J Cancer 99 Pages: 647-654
• [Journal Article] Hypermethylation of the RECK gene predicts poor prognosis in oral squamous cell carcinomas (2008)
  • Author(s): Long, NK, Kato, K, Yamashita, T, Makita, H, Toida, M, Hatakeyama, D, Hara, A, Mori, H, Shibata, T.
  • Journal Title: Oral Oncol. 44 Pages: 1052-1058
• [Journal Article] High frequency of hypermethylation of p14, p15 and p16 in oral pre-cancerous lesions associated with betel-quid chewing in Sri Lanka (2008)
  • Author(s): Takeshima, M, Saitoh, M, Kusano, K, Nagayasu, H, Kurashige, Y, Malsantha, M, Arakawa, T, Takuma, T, Chiba, I, Kaku, T, Shibata, T, Abiko, Y.
  • Journal Title: J Oral Pathol Med 37 Pages: 475-479
• [Journal Article] Effects of green tea polyphenol on methylation status of RECK gene and cancer cell invasion in oral squamous cell carcinoma cells (2008)
  • Author(s): Kato K, Long NK, Makita H, Toida M, Yamashita T, Hatakeyama D, Hara A, Mori H, Shibata T.
  • Journal Title: Br J Cancer 19 ; 99(4) : Pages: 647-54
  • Peer Reviewed
• [Journal Article] Hypermethylation of the RECK gene predicts poor prognosis in oral squamous cell carcinomas. (2008)
  • Author(s): Long NK, Kato K, Yamashita T, Makita H, Toida M, Hatakeyama D, Hara A, Mori H, Shibata T.
  • Journal Title: Oral Oncol. 44 Pages: 1052-1058
  • Peer Reviewed
• [Journal Article] High frequency of hypermethylation of p14, p15 and p16 in oral pre-cancerous lesions associated with betel-quid chewing in Sri Lanka. (2008)
  • Author(s): Takeshima M, Saitoh M, Kusano K, Nagayasu H, Kurashige Y, Malsantha M, Arakawa T, Takuma T, Chiba I, Kaku T, Shibata T, Abiko Y.
  • Journal Title: J Oral Pathol Med. 37 Pages: 475-479
  • Peer Reviewed
• [Journal Article] Hypermethylation of the RECK gene predicts poor prognosis in oral squamous cell carcinomas (2008)
  • Author(s): NK Long, K Kato, T Yamashita, et. al., T Shibata
  • Journal Title: Oral Oncology (in press)
  • Peer Reviewed
• [Journal Article] Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1-and M2-type characteristics (2008)
  • Author(s): N Umemura, et. al., T Shibata
  • Journal Title: J Leukoc Biol. (in press)
  • Peer Reviewed
• [Journal Article] Expression pattern of p63 in oral epithelial lesions and submucous fibrosis associated with betel-quid chewing in Sri Lanka. (2007)
  • Author(s): Haniffa, AM Saitoh M, Abiko, Y, Takeshima M, Yamazaki M, Nagayasu H, Sugiura C, Muthumala M, Kaku T, Chiba I, T Shibata
  • Journal Title: Med Mol Morphol. 40(4) Pages: 203-7
  • NAID: 10024380380
  • Peer Reviewed
• [Journal Article] A prostaglandin E2 receptor subtype EP1-selective antagonist, ONO-8711, suppresses 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis (2007)
  • Author(s): Makita H, Mutoh M, Maruyama T, Yonemoto K, Kobayashi A, Fujituka H, Toida M, shibata T, Miyamoto S, Yasui Y, Suzuki R, Wkabayashi K, Tanaka T
  • Journal Title: Carcinogenesis 28(3) Pages: 677-684
  • Peer Reviewed
• [Journal Article] A prostaglandin E2 receptor subtype EP1-selective antagonist, ONO-8711, suppresses 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis (2007)
  • Author(s): H Makita, et. al., T Shibata
  • Journal Title: Carcinogenesis 28 Pages: 677-84
  • Peer Reviewed
• [Journal Article] Chemopreventice effect of fermented brown rice and rice bran on 4-nitroquinoline 1-oxide-induced oral carcinogenesis in rats. (2007)
  • Author(s): Nguyen KL, Makita H, Yamashita T, Toida M, Kato K, Hatakeyama D, Shibata T
  • Journal Title: Oncol Rep 17 Pages: 879-885
• [Journal Article] A prostablandin E2 receptor subtype EP1-selective antagonist, ONO-8711,suppresses 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis (2007)
  • Author(s): Makita H, Mutoh M, Maruyama T, Yonemoto K, KObayashi A, Fujikura H, Toida M, shibata T, Miyamoto S, Yasui Y, Suzuki R, Wkabayashi K, Tanaka T
  • Journal Title: Carcinogenesis 28 Pages: 677-684
• [Journal Article] Aberrant promoter hypermethylation of p16 and MGMT genes in oral squamous cell carcinomas and the surrounding normal mucosa. (2006)
  • Author(s): Kato K, Hara A, Kuno T, Mori H, Yamashita T, Toida M, Shibata T
  • Journal Title: J Cancer Res Clin Oncol. 132 Pages: 735-743
  • Peer Reviewed
• [Journal Article] Inhibitory effects of fermented brown rice and rice bran on the development of acutehepatitis in Long-Evans Cinnamon rats (2006)
  • Author(s): Shibata T, Nagayasu H, Kitajo H, Arisue M, Yamashita T, Hatakeyama D, Iwasaki T, Kobayashi H.
  • Journal Title: Oncol Rep. 15 Pages: 736-743
• [Journal Article] Aberrant promoter hypermethylation of p16 and MGMT genes in oral squamous cell carcinomas and the surrounding normal mucosa (2006)
  • Author(s): Kato K, Hara A, Kuno T, Mori H, Yamashita T, Toida M, Shibata T.
  • Journal Title: J Cancer Res Clin Oncol. 132 Pages: 735-743
• [Journal Article] Preoperative radiotherapy contributes to induction of proliferative activity of CD8+tumor-infiltrating T-cells in oral squamous cell carcinoma. (2006)
  • Author(s): Suwa T, Saito M, Umemura N, Yamashita T, Toida M, Shibata T, Takami T.
  • Journal Title: Oncol Rep. 5 Pages: 757-763
• [Presentation] RECK遺伝子のメチル化と予後との相関および脱メチル化による浸潤制御の可能性 (2009)
  • Author(s): 加藤恵三, et al 7名
  • Organizer: 第63回日本口腔科学会総会
  • Place of Presentation: アクトシティー浜松(浜松市)
  • Year and Date: 2009-04-17
• [Presentation] RECK遺伝子のメチル化と予後との相関および脱メチル化による浸潤制御の可能性 (2009)
  • Author(s): 加藤恵三, et al7名
  • Organizer: 第63回 日本口腔科学総会
  • Place of Presentation: アクトシティー浜松(浜松市)
  • Year and Date: 2009-04-17
• [Presentation] (2)K Kato, et al, T Shibata Examination of Hypermethylation of RECK gene in squamous cell carcinoma celllines and effect of antimethylation agent (2007)
  • Author(s): K Kato, et al
  • Organizer: 89th回AAOMS
  • Place of Presentation: Honolulu City
  • Year and Date: 2007-09-10
• [Presentation] Examination of Hypermethylation of RECK gene in squamous cell carcinoma celllines and effect of antimethylation agent (2007)
  • Author(s): K Kato, et. al., T Shibata
  • Organizer: 89回 アメリカ口腔外科学会総会(AAOMS)
  • Place of Presentation: Honolulu City
  • Year and Date: 2007-09-10