Embryonic basal cells at squamous columnar junction as the cells of origin for Barrett esophagus

• Project/Area Number: 19K24058
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0906:Surgery related to the biological and sensory functions and related fields
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Terayama Masayoshi 国立研究開発法人国立国際医療研究センター, その他部局等, 外科 レジデント (20843014)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: バレット食道 / 組織幹細胞 / 食道胃接合部 / 食道 / 食道-胃接合部 / 胚性上皮細胞 / 食道癌

Outline of Research at the Start

食道-胃接合部には、食道重層扁平上皮細胞の供給源となる基底細胞や、胃腺底部に存在する幹細胞とは異なる形質を有した“胚性上皮細胞” が存在する。近年、マウスモデルを用いた研究により、この“胚性上皮細胞”がバレット上皮の起源となることが示されたが、その生理的・病理的な細胞動態と細胞機能については不明な点が多い。本研究では申請者らが独自に見出した“胚性上皮細胞”に限局して発現する分子を指標として用いることで、バレット食道発症機構の解明を目指す。

Outline of Final Research Achievements

We immunologically examined the expression of Glutathione S-transferase Omega 2 (GSTO2), normally expressed in the nethermost cells of esophageal mucosa, and found GSTO2-positive cell population in glands of esophago-gastric junctions. Immuno-histochemical staining of 87 resected specimens by esophagectomy revealed that GSTO2 expressed in 13 of 27 (48%) esophageal adenocarcinoma (EAC) cases and 13 of 62 (21%) esophageal squamous cell carcinoma (ESCC) cases, respectively. To examine the function of GSTO2 in ESCC and EAC, we prepared stable GSTO2-transfected and mock-transfected cells which possessing empty vector. Forced expression of GSTO2 inhibited tumor cell growth and suppressed the membrane expression of E-cadherin, a marked epithelial marker, in ESCC but did not affect EAC cell functions. These results suggest that GSTO2 may have different roles in carcinogenesis between ESCC and EAC.

Academic Significance and Societal Importance of the Research Achievements

バレット食道は食道腺癌の発生母地として知られるが、バレット食道の発生起源とされる”胚性上皮細胞”の挙動と機能的変化については、特異的分子マーカーの同定に至らず、解明が進んでいない。本研究の学術的・社会的意義は、”胚性上皮細胞”に限局して発現し、腺癌発症に相関している分子を同定したことである。更に、本分子の発現制御機構並びに分子機能は食道扁平上皮と腺上皮で異なることを明らかにしており、食道扁平上皮が腺上皮へと置き換わるバレット食道の分子病態解明に繋がる、重要な知見が得られた。

Research Products

• [Journal Article] Expression status of serine protease 27: A prognostic marker for esophageal squamous cell carcinoma treated with preoperative chemotherapy/chemoradiotherapy (2021)
  • Author(s): Kataoka, A, Yamada K, Hagiwara T, Terayama M, Sugimoto T, Nohara K, Igari T, Yokoi C, Kawamura YI.
  • Journal Title: Annals of Surgical Oncology Volume: 印刷中 Issue: 9 Pages: 5373-5381
  • DOI: 10.1245/s10434-020-09550-y
  • Peer Reviewed / Open Access
• [Journal Article] Glutathione S-transferase Omega 2 Regulates Cell Growth and the Expression of E-cadherin via Post-Transcriptional Downregulation of β-Catenin in Human Esophageal Squamous Cells (2019)
  • Author(s): Terayama M, Yamada K, Hagiwara T, Inazuka F, Sezaki T, Igari T, Yokoi C, Nohara K, Soma D, Dohi T, Kawamura YI.
  • Journal Title: Carcinogenesis Volume: 印刷中 Issue: 7 Pages: 875-886
  • DOI: 10.1093/carcin/bgz189
  • Peer Reviewed
• [Presentation] Glutathione S-transferase omega 2 (GSTO2) suppresses cell growth and membrane localization of E-cadherin via p38MAPK signaling pathway in human esophageal squamous cells (2020)
  • Author(s): Masayoshi Terayama, Kazuhiko Yamada, Teruki Hagiwara, Taeko Dohi, Norihiro Kokudo, and Yuki I. Kawamura
  • Organizer: Digestive Disease Week 2020
  • Int'l Joint Research
• [Presentation] GSTO2, a novel tumor suppressor gene, modulates intercellular metabolism of esophageal squamous cell carcinoma (2020)
  • Author(s): Masayoshi Terayama, Kazuhiko Yamada, Norihiro Kokudo, and Yuki I. Kawamura
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 食道上皮細胞の接着性を制御するGSTO2 (2020)
  • Author(s): 寺山仁祥 、山田和彦 、萩原輝記 、中野美和 、土肥多惠子 、國土典宏 、河村由紀
  • Organizer: 第74回日本食道外科学会学術集会
• [Presentation] Glutathione S-transferase omega 2 (GSTO2) suppresses cell growth and membrane localization of E-cadherin via p38MAPK signaling pathway in human esophageal squamous cells (2020)
  • Author(s): Masayoshi Terayama, Kazuhiko Yamada, Teruki Hagiwara, Taeko Dohi, Norihiro Kokudo, and Yuki I. Kawamura
  • Organizer: Digestive Disease Week 2020
  • Int'l Joint Research
• [Presentation] 食道上皮細胞の接着性を制御するGSTO2 (2020)
  • Author(s): Masayoshi Terayama, Kazuhiko Yamada, Teruki Hagiwara, Miwa Nakano, Taeko Dohi, Norihiro Kokudo, and Yuki I. Kawamura
  • Organizer: 第74回 日本食道外科学会
• [Presentation] 3.GSTO2, a novel tumor suppressor gene, regulates the expression of E-cadherin in esophageal squamous cell carcinoma. (2019)
  • Author(s): Masayoshi Terayama, Kazuhiko Yamada, Norihiro Kokudo, and Yuki I. Kawamura
  • Organizer: 第78回 日本癌学会学術総会