Molecular functions of a novel gene exclusively expressed in esophageal basal cells

• Project/Area Number: 19K08457
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Kawamura Yuki I. 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, 室長 (10392391)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 食道扁平上皮 / /幹細胞 / 幹細胞

Outline of Research at the Start

消化管粘膜は、幹細胞から上皮細胞が新しく供給されることによりその恒常性が保たれている。胃・腸では幹細胞マーカーであるLgr5、Bmi1等が同定されており、幹細胞のheterogeneityと共にそれらの機能の詳細な解明が進んでいる。これに対し、食道粘膜では基底部に存在する基底細胞が、非角化重層扁平上皮細胞に分化しながら管腔側へと移動することが知られているが、胃や腸の幹細胞に相当する細胞が存在するか、その特異的分子マーカーの同定も含めて詳細は明らかにされていない。本研究の目的は、我々が新たに見出した、基底細胞に限局して発現する分子群の幹細胞機能への寄与について明らかにすることである。

Outline of Final Research Achievements

No useful markers to identify stem cells in esophageal mucosa have been reported, whereas Lgr5 and Bmi1 were well-known as stem cell markers of stomach and intestine. In addition, previous reports revealed that all esophageal basal cells divide at a similar rate, suggesting that there are no slow-cycling stem cells in murine esophagus. In this study, we examined molecular functions of glutathione S-transferase omega 2 (GSTO2), because its expression was confined to basal cells in human esophageal mucosa. We found that basal cells in the human esophagus comprise heterogeneous cell populations, such as proliferative cell marker Ki67+ and Ki67－ cells, with the latter expressing GSTO2. We also illustrated the function of GSTO2 in regulating cell growth as well as differentiation. These results suggest that GSTO2 plays an important role in maintaining the homeostasis of esophageal epithelia along with its significance as a novel marker for esophageal stem cells.

Academic Significance and Societal Importance of the Research Achievements

消化管粘膜は、幹細胞から上皮細胞が新しく供給されることで恒常性が保たれている。本研究により、食道にも胃や腸のように、細胞回転速度の異なるヘテロな細胞集団が存在することが明らかとなった。より細胞回転の遅い、所謂”dormant”幹細胞集団を見分けるマーカーの同定は、食道幹細胞研究に対する学術的貢献度が高いと考えられる。幹細胞の理解は、組織傷害に対する幹細胞を用いた治療法の開発にも繋がると期待され、社会的意義も大きい。

Research Products

• [Journal Article] Loss of GSTO2 contributes to cell growth and mitochondria function via the p38 signaling in lung squamous cell carcinoma (2021)
  • Author(s): Sumiya Ryusuke、Terayama Masayoshi、Hagiwara Teruki、Nakata Kazuaki、Sekihara Keigo、Nagasaka Satoshi、Miyazaki Hideki、Igari Toru、Yamada Kazuhiko、Kawamura Yuki I.
  • Journal Title: Cancer Science Volume: 113 Issue: 1 Pages: 195-204
  • DOI: 10.1111/cas.15189
  • Peer Reviewed / Open Access
• [Journal Article] ASO Author Reflections: Serine Protease 27 is a Novel Prognostic Indicator for Esophageal Squamous Cell Carcinoma with Preoperative Treatment (2021)
  • Author(s): Kataoka Atsuko、Yamada Kazuhiko、Kawamura Yuki I.
  • Journal Title: Annals of Surgical Oncology Volume: 28 Issue: 9 Pages: 5382-5383
  • DOI: 10.1245/s10434-020-09580-6
  • Peer Reviewed
• [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] The N-terminal region of Jaw1 has a role to inhibit the formation of organized smooth endoplasmic reticulum as an intrinsically disordered region (2021)
  • Author(s): Kozono T, Sato H, Okumura W, Jogano C, Tamura-Nakano M, Kawamura YI, Rohrer J, Tonozuka, T, Nishikawa A.
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 753-753
  • DOI: 10.1038/s41598-020-80258-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] DNA hypermethylation and silencing of glutathione S-transferase omega 2 (GSTO2) in non-small cell lung cancer. (2021)
  • Author(s): Sumiya R, Hagiwara T, Nagasaka S, Kawamura YI.
  • Organizer: The 25th Congress of the Asian Pacific Society of Respirology (APSR)
  • Int'l Joint Research
• [Presentation] Glutathione S-Transferase omega 2 (GSTO2) regulates cell growth and mitochondrial oxidative phosphorylation in lung squamous cell carcinoma. (2021)
  • Author(s): 住谷隆輔、寺山仁祥、山田和彦、國土典宏、河村 由紀
  • Organizer: 第80回 日本癌学会総会
• [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): Terayama M, Yamada K, Hagiwara T, Dohi T, Kokudo N, Kawamura YI.
  • Organizer: Digestive Disease Week Annual Meeting (米国消化器病週間学会)
  • Int'l Joint Research
• [Presentation] Glutathione S-transferase omega 2 (GSTO2) is a novel tumor suppressor gene of human lung squamous cell carcinoma (2020)
  • Author(s): Sumiya R, Terayama M, Hagiwara T, Sekihara K, Nagasaka S, Yamada K, Kokudo N, Kawamura YI.
  • Organizer: American Association for Cancer Research (米国癌学会)
  • Int'l Joint Research
• [Presentation] 食道扁平上皮癌における新規癌抑制遺伝子GSTO2は細胞内代謝を制御することで増殖を制御する (2020)
  • Author(s): 寺山 仁祥、山田 和彦、國土 典宏、河村 由紀．
  • Organizer: 日本癌学会総会
• [Presentation] The characterization of the function of glutathione S-transferase omega 2 (GSTO2) indicated the presence of putative quiescent stem cells in human esophagus (2019)
  • Author(s): Terayama M, Yamada K, Hagiwara T, Inazuka F, Dohi T, Kokudo N, Kawamura YI.
  • Organizer: Digestive Disease Week Annual Meeting (米国消化器病週間学会)
  • Int'l Joint Research
• [Presentation] E-cadherin expression correlates with progression of esophageal squamous cell carcinoma (2019)
  • Author(s): Koda H, Yamada K, Terayama M, Sumiya R, Nohara K, Enomoto N, Kataoka A, Mita H, Takemura N, Kiyomatsu T, Kokudo N, Kawamura YI.
  • Organizer: The Annual Meeting of the European Society for Diseases of the Esophagus (欧州食道会議)
  • Int'l Joint Research
• [Presentation] 食道扁平上皮癌における新規癌抑制遺伝子GSTO2はE-カドヘリンの発現を抑制する (2019)
  • Author(s): 寺山 仁祥、山田 和彦、國土 典宏、河村 由紀．
  • Organizer: 日本癌学会総会