Research on the mechanism of acetaldehyde related esophageal carcinogenesis and clinical application for prevention

• Project/Area Number: 24590917
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: MUTO Manabu 京都大学, 医学(系)研究科(研究院), 教授 (40360698)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 癌 / 臨床 / アルコール

Outline of Final Research Achievements

In this study, we revealed that acetaldehyde exposure in vitro causes acetaldehyde derived DNA adducts formation in the esophageal squamous epithelium, phosphorylation of p53 protein and cellular senescence. In human, the extent of DNA damage induced by acetaldehyde exposure was also correlated with the degree of change in the esophageal precancerous dysplasia. Inhibition of ALDH2 expression by siRNA increased DNA damage. Long-term exposure of acetaldehyde to the esophageal squamous epithelium in vitro affected esophageal squamous differentiation (keratinization), and caused confusion of polarity of nuclei of basal or parabasal cell, ballooning and parakeratotic changes, it was similar to the dysplastic squamous epithelium.

Research Products

• [Journal Article] Phosphatidylcholine with arachidonic acid was increased in the submucosal microinvasive region of hypopharyngeal carcinoma (2015)
  • Author(s): Seiji Ishikawa, Ichiro Tateya, Takahiro Hayasaka, Noritaka Masaki, Shigeru Hirano, Morimasa Kitamura, Manabu Muto, Shuko Morita, Mitsutoshi Setou, Juichi Ito
  • Journal Title: Cancer science Volume: in press
  • Peer Reviewed
• [Journal Article] A randomized controlled Phase II/III study comparing endoscopic balloon dilation combined with steroid injection versus radial incision and cutting combined with steroid injection for refractory anastomotic stricture after esophagectomy: Japan Clinical Oncology Group Study JCOG1207 (2015)
  • Author(s): Kataoka Kozo, Aoyama Ikuo, Mizusawa Junki, Eba Junko, Minashi Keiko, Yano Tmonori, Tanaka Masaki, Hanaoka Noboru, Katayama Hiroshi, Takizawa Kohei, Fukuda Haruhiko and Manabu Muto, on behalf of the Gastrointestinal Endoscopy Study Group(GIESG)of the Japan Clinical Oncology Group
  • Journal Title: Jpn J Clin Oncol Volume: 45 Issue: 4 Pages: 385-389
  • DOI: 10.1093/jjco/hyv006
  • Peer Reviewed
• [Journal Article] Factors associated with the presence of multiple Lugol-voiding lesions in patients with esophageal squamous-cell carcinoma (2014)
  • Author(s): Katada C, Muto M, Tanabe S, Higuchi K, Sasaki T, Azuma M, Ishido K, Katada N, Sakuramoto S, Yamashita K, Masaki T, Nakayama M, Okamoto M, Koizumi W
  • Journal Title: Dis Esophagus Volume: 27 Issue: 5 Pages: 457-462
  • DOI: 10.1111/j.1442-2050.2012.01429.x
  • Peer Reviewed
• [Journal Article] Magnifying endoscope with NBI topredict the depth of invasion in laryngo-pharyngeal cancer (2014)
  • Author(s): Ichiro Tateya, Shuko Morita, Manabu Muto, Shinichi Miyamoto, Tomomasa Hayashi, Makiko Funakoshi, Ikuo Aoyama, Shigeru Hirano, Morimasa Kitamura, Seiji Ishikawa, Yo Kishimoto, Mami Morita, Patnarin Mahattanasakul, Satoshi Morita, Juishi Ito
  • Journal Title: Laryngoscope Volume: 2014 Issue: 5 Pages: 1124-1129
  • DOI: 10.1002/lary.25035
  • Peer Reviewed
• [Journal Article] Impairment of aldehyde dehydrogenase 2 increases accumulation of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion (2014)
  • Author(s): Yoshiyuki Yukawa, Shinya Ohashi, Yusuke Amanuma, Yukie Nakai, Mihoko Tsurumaki, Osamu Kikuchi, Shin’ichi Miyamoto, Tsunehiro Oyama, Toshihiro Kawamoto, Tsutomu Chiba, Tomonari Matsuda, Manabu Muto
  • Journal Title: Am J Cancer Res Volume: 4 Pages: 279-284
  • Peer Reviewed
• [Journal Article] Preclinical validation of talaporfin sodium-mediated photodynamic therapy for esophageal squamous cell carcinoma (2014)
  • Author(s): Shinya Ohashi, Osamu Kikuchi, Mihoko Tsurumaki, Yukie Nakai, Daisuke Kuriyama, Hiroi Kasai, Takahiro Horimatsu, Shin’ichi Miyamoto, Akira Shimizu, Tsutomu Chiba, Manabu Muto
  • Journal Title: PLOS ONE Volume: 9 Issue: 8 Pages: e103126-e103126
  • DOI: 10.1371/journal.pone.0103126
  • Peer Reviewed / Open Access
• [Journal Article] Salvage photodynamic therapy is an effective and safe treatment for patients with local failure after definitive chemoradiotherapy for esophageal squamous cell carcinoma (2014)
  • Author(s): Yoko Mashimo, Yasumasa Ezoe, Kosuke Ueda, Yoshinao Ozaki, Yusuke Amanuma, Ikuo Aoyama, Takahiro Horimatsu, Shuko Morita, Shinichi Miyamoto, Tomonori Yano, Koji Higashino, Tsutomu Chiba, Manabu Muto
  • Journal Title: Journal of Cancer Therapy (JCT) Volume: 5 Issue: 07 Pages: 647-656
  • DOI: 10.4236/jct.2014.57073
  • Peer Reviewed
• [Journal Article] Multimodal endoscopic treatment for delayed severe esophageal stricture caused by incomplete stent removal (2014)
  • Author(s): Setoyma T, Miyamoto S, Horimatsu T, Morita S, Ezoe Y, Muto M, Watanabe G, Tanaka E, Chiba T
  • Journal Title: Dis Esophagus Volume: 2 Issue: 2 Pages: 7112-115
  • DOI: 10.1111/dote.12041
  • Peer Reviewed
• [Journal Article] Impairment of aldehyde dehydrogenase 2 increases accumulation of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion. (2014)
  • Author(s): Yoshiyuki Yukawa, Shinya Ohashi, Yusuke Amanuma, Yukie Nakai, Mihoko Tsurumaki, Osamu Kikuchi, Shin’ichi Miyamoto, Tsunehiro Oyama, Toshihiro Kawamoto, Tsutomu Chiba, Tomonari Matsuda, Manabu Muto.
  • Journal Title: Am J Cancer Res Volume: -
  • Peer Reviewed
• [Journal Article] Salvage photodynamic therapy is an effective and safe treatment for patients with local failure after definitive chemoradiotherapy for esophageal squamous cell carcinoma. (2014)
  • Author(s): Yoko Mashimo, Yasumasa Ezoe, Kosuke Ueda, Yoshinao Ozaki, Yusuke Amanuma, Ikuo Aoyama, Takahiro Horimatsu, Shuko Morita, Shinichi Miyamoto, Tomonori Yano, Koji Higashino, Tsutomu Chiba, Manabu Muto.
  • Journal Title: Journal of Cancer Therapy Volume: -
  • Peer Reviewed
• [Journal Article] Phosphatidylcholine with arachidonic acid was increased in the submucosal microinvasive region of hypopharyngeal carcinoma. (2014)
  • Author(s): Seiji Ishikawa, Ichiro Tateya, Takahiro Hayasaka, Noritaka Masaki, Shigeru Hirano, Morimasa Kitamura, Manabu Muto, Shuko Morita, Mitsutoshi Setou, Juichi Ito.
  • Journal Title: Cancer science Volume: -
  • Peer Reviewed
• [Journal Article] Elimination of esophageal multiple precancerous lesions by chemotherapy: potential chemoprevention of metachronous multiple cancer development after curative treatment. (2012)
  • Author(s): Yoshiyuki Yukawa, Manabu Muto, et al
  • Journal Title: Esophagus Volume: 9 Issue: 4 Pages: 203-209
  • DOI: 10.1007/s10388-012-0339-3
  • NAID: 40019542046
  • Peer Reviewed
• [Journal Article] Combination of ADH1B*2/ALDH2*2 polymorphisms alters acetaldehyde-derived DNA damage in the blood of Japanese alcoholics (2012)
  • Author(s): Yukawa, Y. et al.
  • Journal Title: Cancer Science Volume: 103 Issue: 9 Pages: 1651-1655
  • DOI: 10.1111/j.1349-7006.2012.02360.x
  • Peer Reviewed
• [Journal Article] Stability of acetaldehyde-derived DNA adduct in vitro. (2012)
  • Author(s): Hori K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 423 Issue: 4 Pages: 642-646
  • DOI: 10.1016/j.bbrc.2012.05.158
  • Peer Reviewed
• [Presentation] 食道上皮におけるALDH2発現誘導アセトアルデヒドに起因する食道上皮傷害を制御する (2014)
  • Author(s): 大橋 真也、天沼 祐介、鶴巻美穂子、中井由起恵、菊池 理、宮本 心一、千葉 勉、松田 知成、武藤 学
  • Organizer: 第68回日本食道学会学術集会
  • Place of Presentation: 東京ドームホテル（東京都文京区）
  • Year and Date: 2014-07-03
• [Presentation] Induction of aldehyde dehydrogenase-2(Aldh-2) expression in esophageal epithelial cells suppresses the acetaldehyde-mediated DNA damage (2014)
  • Author(s): Yusuke Amanuma, Shinya Ohashi, Mihoko Tsurumaki, Yukie Nakai, Shin’ichi Miyamoto, Tsutomu Chiba, Hiroshi Nakagawa, Tomonari Matsuda, Manabu Muto
  • Organizer: Digestive Disease Week2014 (DDW2014)
  • Place of Presentation: Chicago Illinois (USA)
  • Year and Date: 2014-05-03 – 2014-05-06
• [Presentation] 食道扁平上皮におけるアルコール関連発癌機序の解明 (2014)
  • Author(s): 天沼 裕介、大橋 真也、武藤 学
  • Organizer: 第100回日本消化器病学会総会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2014-04-23
• [Presentation] Aldehyde dehydrogenase-2 regulates esophageal epithelial cell senescence checkpoint functions activated by an alcohol metabolite. (2013)
  • Author(s): Yusuke Amanuma, Shinya Ohashi, Manabu Muto.
  • Organizer: Digestive Disease Week (AGA)
  • Place of Presentation: Orange County Convention Center (Orland, FL, USA)
• [Presentation] Regulation of chemotherapy resistance through epithelial-mesenchymal transition by Zinc finger E-box-binding proteins ZEB1 in esophageal squamous cell carcinoma (2013)
  • Author(s): Shinya Ohashi, Osamu Kikuchi, Yasumasa Ezoe, Manabu Muto
  • Organizer: Grobal Academic Program 2013 MD Anderson Cancer Center
  • Place of Presentation: MD Anderson Cancer Center/1MC3 Conference Center (Houston, TX, USA)
• [Presentation] 食道扁平上皮で誘導されるALDH2はアセトアルデヒドによる細胞老化を制御する (2013)
  • Author(s): 天沼 裕介、大橋 真也、宮本 心一、千葉 勉、武藤 学
  • Organizer: 第67回日本食道学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
• [Presentation] Aldehyde dehydrogenase-2 regulates esophageal epithelial cell senescence checkpoint functions activated by an alcohol metabolite (2013)
  • Author(s): Yusuke Amanuma, Shinya Ohashi, Manabu Muto
  • Organizer: Digestive Disease Week 2013 (AGA)
  • Place of Presentation: Orange County Convention Center(Orland)
• [Presentation] 食道扁平上皮で誘導されるALDH2はアセトアルデヒドによる細胞老化を制御する (2013)
  • Author(s): 天沼 祐介、大橋 真也、武藤 学
  • Organizer: 第67回日本食道学会
  • Place of Presentation: 大阪国際会議場
• [Presentation] 食道におけるアセトアルデヒド由来DNA付加体蓄積と食道発がんの関係 (2012)
  • Author(s): 湯河良之、江副康正、武藤学
  • Organizer: 第66回日本食道学会
  • Place of Presentation: 軽井沢プリンスホテル ウエスト
• [Patent(Industrial Property Rights)] 終末呼気を利用する高精度なアルデヒド分解酵素活性遺伝子型判別方法、扁平上皮癌発生危険度判定方法、扁平上皮癌発生危険度判定装置、及びプログラム (2013)
  • Inventor(s): 武藤学、青山育雄、田中克之、花田真理子
  • Industrial Property Rights Holder: 京都大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-10-31