Induction of predisposition to squamous cell carcinogenesis in esophagus by genome editing of metabolic enzymes

• Project/Area Number: 18K19577
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Kanazawa University
• Principal Investigator: MINAMOTO Toshinari 金沢大学, がん進展制御研究所, 教授 (50239323)
• Co-Investigator(Kenkyū-buntansha): 大黒 多希子 金沢大学, 学際科学実験センター, 教授 (30767249)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 食道 / 扁平上皮がん / 発がん / 代謝酵素 / ゲノム編集 / 糖代謝酵素

Outline of Final Research Achievements

This study attempted to generate cellular and mouse models susceptible to esophageal squamous cell (ESC) carcinogenesis by genome editing of glycogen synthase (GS) and GS kinase (GSK)3β, both regulating glycogen metabolism, based on the hypothesis that intracellular glycogen depletion is the critical selective pressure for cellular transformation and malignant evolution in ESC carcinogenesis. By genome editing technologies including CRISPR-Cas9, we could deplete GS or transduce the constitutively active mutant of GSK3β in patient-derived normal ESCs and C57BL/6 mouse esophageal squamous mucosa. Long term observations for changes in glycogen metabolism and preneoplastic phenotypes in these genome-edited human ESCs and mouse model established in the term of this research project are necessary to clarify an induction of susceptibility to ESC carcinogenesis.

Academic Significance and Societal Importance of the Research Achievements

本研究は、食道と頭頸部扁平上皮がんの連鎖に代表されるフィールドがん化現象（共通のがん誘発因子により複数の領域や組織にまたがってひろく発がんする状態）と、細胞、組織の分化や発がんにおけるグリコーゲン合成系の新たな生物学的機能の一端を拓く可能性が期待される。食道がんの90%を占める扁平上皮がんの発がん特性を外挿する自然発がんモデルの構築に新たな視点を附与することにより、健康被害を来たす本疾患の病態理解、早期診断や治療法開発に寄与することが期待される。

Research Products

• [Journal Article] Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer (2020)
  • Author(s): Ailiken Guzhanuer、Kitamura Kouichi、Hoshino Tyuji、Satoh Mamoru、Tanaka Nobuko、Minamoto Toshinari、Rahmutulla Bahityar、Kobayashi Sohei、Kano Masayuki、Tanaka Tomoaki、Kaneda Atsushi、Nomura Fumio、Matsubara Hisahiro、Matsushita Kazuyuki
  • Journal Title: Oncogenesis Volume: 9 Issue: 2 Pages: 26-26
  • DOI: 10.1038/s41389-020-0205-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Significance of gene mutations in the Wnt signaling pathway in traditional serrated adenomas of the colon and rectum (2020)
  • Author(s): Nakanishi, H. Sawada, T. Kaizaki, Y. Ota, R. Suzuki, H. Yamamoto, E. Aoki, H. Eizuka, M. Hasatani, K. Takahashi, N. Inagaki, S. Ebi, M. Kato, H. Kubota, E. Kataoka, H. Takahashi, S. Tokino, T. Minamoto, T. Sugai, T. Sasaki, Y.
  • Journal Title: PLoS One Volume: 15 Issue: 2 Pages: e0229262-e0229262
  • DOI: 10.1371/journal.pone.0229262
  • Peer Reviewed / Open Access
• [Journal Article] NF-kB activation promotes gastric tumorigenesis through the expansion of SOX2-positive epithelial cells. (2019)
  • Author(s): Echizen K, Horiuchi K, Aoki Y, Yamada Y, Minamoto T, Oshima H, and Oshima M.
  • Journal Title: Oncogene Volume: accepted Issue: 22 Pages: 4250-4263
  • DOI: 10.1038/s41388-019-0702-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-FIRΔexon2, a splicing variant form of PUF60, auto-antibody is detected in the sera of esophageal squamous cell carcinoma. (2019)
  • Author(s): Kobayashi S, Hiwasa T, Ishige T, Rahmutulla B, Kano M, Hoshino T, Minamoto T, Shimada H, Nomura F, Matsubara H, Matsushita K.
  • Journal Title: Cancer Sci. Volume: 4 Issue: 6 Pages: 1-10
  • DOI: 10.1111/cas.14024
  • Peer Reviewed / Open Access
• [Journal Article] Identification of GSK3β inhibitor kenpaullone as a temozolomide enhancer against glioblastoma (2019)
  • Author(s): Kitabayashi Tomohiro、Dong Yu、Furuta Takuya、Sabit Hemragul、Jiapaer Shabierjiang、Zhang Jiakang、Zhang Guangtao、Hayashi Yasuhiko、Kobayashi Masahiko、Domoto Takahiro、Minamoto Toshinari、Hirao Atsushi、Nakada Mitsutoshi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 10049-10049
  • DOI: 10.1038/s41598-019-46454-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glycogen synthase kinase 3β as a potential therapeutic target in synovial sarcoma and fibrosarcoma (2019)
  • Author(s): Abe Kensaku、Yamamoto Norio、Domoto Takahiro、Bolidong Dilireba、Hayashi Katsuhiro、Takeuchi Akihiko、Miwa Shinji、Igarashi Kentaro、Inatani Hiroyuki、Aoki Yu、Higuchi Takashi、Taniguchi Yuta、Yonezawa Hirotaka、Araki Yoshihiro、Aiba Hisaki、Minamoto Toshinari、Tsuchiya Hiroyuki
  • Journal Title: Cancer Science Volume: 111 Issue: 2 Pages: 429-440
  • DOI: 10.1111/cas.14271
  • Peer Reviewed / Open Access
• [Journal Article] Tumor p16INK4 gene expression and prognosis in colorectal cancer (2019)
  • Author(s): Kitamura H, Takemura H, Minamoto T
  • Journal Title: Oncol Rep Volume: 41 Pages: 1367-1376
  • DOI: 10.3892/or.2018.6884
  • Peer Reviewed
• [Journal Article] Colorectal cancer cells require glycogen synthase kinase-3β for sustaining mitosis via translocated promoter region (TPR)-dynein interaction (2018)
  • Author(s): Dewi Firli R.P.、Domoto Takahiro、Hazawa Masaharu、Kobayashi Akiko、Douwaki Takayuki、Minamoto Toshinari、Wong Richard W.
  • Journal Title: Oncotarget Volume: 9 Issue: 17 Pages: 13337-52
  • DOI: 10.18632/oncotarget.24344
  • NAID: 120006452368
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice. (2018)
  • Author(s): Han TS, Voon DC, Oshima H, Nakayama M, Echizen K, Sakai E, Yong ZWE, Murakami K, Yu L, Minamoto T, Ock CY, Jenkins BJ, Kim SJ, Yang HK, Oshima M
  • Journal Title: Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice Volume: 156 Issue: 4 Pages: 1140-1155
  • DOI: 10.1053/j.gastro.2018.11.059
  • NAID: 120006621945
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Glycogen synthase kinase-3β is a new therapeutic target in soft tissue sarcoma: a basic research. (2019)
  • Author(s): Kensaku Abe, Norio Yamamoto, Takahiro Domoto, Katsuhiro Hayashi, Akihiko Takeuchi, Shinji Miwa, Kentaro Igarashi, Takashi Higuchi, Yuta Taniguchi, Hirotaka Yonezawa, Yoshihiro Araki, Toshinari Minamoto, Hiroyuki Tsuchiya.
  • Organizer: American Academy of Orthopaedic Surgeons (AAOS) Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] 膵がん細胞の薬剤耐性化に伴うがん悪性形質とGSK3βの病理作用． (2019)
  • Author(s): 堂本貴寛, 竹中 哲, 宮下知治, 上原将大, 竹内 修, 太田哲生, 源 利成.
  • Organizer: 第28回日本癌病態治療研究会
• [Presentation] heat shock protein、Fam107BはGSK3βを介して大腸がん細胞の遊走性を抑制する． (2019)
  • Author(s): 小泉惠太，堂本貴寛，中尾啓子，源 利成，中島日出夫．
  • Organizer: 第28回日本癌病態治療研究会
• [Presentation] 膵がん細胞のゲムシタビン耐性化においてGSK3βは幹細胞性と浸潤能を増強する． (2019)
  • Author(s): 堂本貴寛, 竹中 哲, 宮下知治, 上原将大, 太田哲生, 源 利成．
  • Organizer: 第28回日本がん転移学会学術集会・総会
• [Presentation] GSK3βは膵がんの幹細胞性，浸潤能，薬剤耐性獲得にそれぞれ連関する． (2019)
  • Author(s): 堂本貴寛，宮下知治，竹中 哲，上原将大，太田哲夫，源 利成．
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 食道扁平上皮がんのGSK3β阻害は細胞周期停止とアポトーシスを誘導する． (2019)
  • Author(s): ディリラバ ボリドン，堂本貴寛，上原将大，奥村智之，遠藤良夫，イリア ピコ，宮下知治，中田光俊，源 利成．
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 膵がんのゲムシタビン獲得耐性はglycogen synthase kinase (GSK)-3βに依存する． (2019)
  • Author(s): 上原将大，堂本貴寛，竹中 哲，ディリラバ ボリドン，ピコ イリア，島崎猛夫，宮下知治，太田哲生，源 利成．
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 抗がん剤ゲムシタビンによる膵がん細胞のエクソソーム分泌及びエクソソーム表面マーカーへの影響． (2019)
  • Author(s): 山本聡子，松尾洋一，林 祐一，源 利成，島崎猛夫．
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 非乳頭十二指腸腫瘍におけるDNAメチル化解析． (2019)
  • Author(s): 澤田 武, 太田亮介, 鈴木 拓, 津山 翔, 八尾隆史, 中西宏佳, 山本英一郎, 久保田英嗣, 片岡洋望, 佐々木泰史, 源 利成．
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Methylation analysis of non-ampullary duodenal precancerous lesions. (2019)
  • Author(s): Ryosuke Ota, Takeshi Sawada, Hiromu Suzuki, Sho Tsuyama, Takashi Yao, Eiichiro Yamamoto, Hiroyoshi Nakanishi, Shigetsugu Tsuji, Naohiro Yoshida, Hisashi Doyama, Hiroshi Minato, Kenkei Hasatani, Yasuharu Kaizaki, Eiji Kubota, Hiromi Kataoka, Yasushi Sasaki, Toshinari Minamoto.
  • Organizer: 27th United European Gastroenterology (UEG) Week 2019
  • Int'l Joint Research
• [Presentation] 膵癌細胞エクソソームの抗がん剤による動態変化とその生物学的意義． (2019)
  • Author(s): 島崎猛夫，山本聡子，林 祐一，松尾洋一，源 利成．
  • Organizer: 第30回日本消化器癌発生学会総会
• [Presentation] 十二指腸非乳頭部腫瘍における遺伝子メチル化と変異解析． (2019)
  • Author(s): 澤田 武, 太田亮介, 鈴木 拓, 津山 翔, 八尾隆史, 中西宏佳, 波佐谷兼慶, 海崎泰治, 吉田尚弘, 辻 重継, 土山寿志, 湊 宏, 山本英一郎, 久保田英嗣, 片岡洋望, 佐々木泰史, 源 利成．
  • Organizer: 第30回日本消化器癌発生学会総会
• [Presentation] バレット食道から発癌過程での微小環境の変化とGSK3β阻害による抑制 (2018)
  • Author(s): 宮下知治，源 利成，太田哲生
  • Organizer: 第104回日本消化器病学会総会
• [Presentation] Inhibitor of GSK3β impedes the development of reflux-induced esophageal cancer in a surgical rat model (2018)
  • Author(s): Miyashita T, Minamoto T, et al.
  • Organizer: Digestive Disease Week (DDW) 2018
  • Int'l Joint Research
• [Presentation] GSK3βは大腸がんのがん原性オートファジーを促進する (2018)
  • Author(s): 堂本貴寛，ほか
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 大腸鋸歯状病変における，遺伝子変異，コピー数変化，DNAメチル化の統合解析 (2018)
  • Author(s): 澤田 武，ほか
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Integrative analysis of gene mutations and DNA methylation in colorectal serrated lesions (2018)
  • Author(s): Sawada T, et al.
  • Organizer: 26th United European Gastroenterology (UEG) Week 2018
  • Int'l Joint Research