Establishment of a novel mouse colon cancer disease model with different genome instability useful for subclass classification

• Project/Area Number: 25293284
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Department of Clinical Research, National Hospital Organization Kure Medical Center (2016); Hiroshima University (2013-2015)
• Principal Investigator: Hinoi Takao 独立行政法人国立病院機構(呉医療センター臨床研究部), その他部局等, 臨床研究部室長 (10444689)
• Co-Investigator(Renkei-kenkyūsha): SOTOMARU Yusuke 広島大学, 自然科学研究支援開発センター, 教授 (90309352) ; IKENOUE Tsuneo 東京大学, 医科学研究所, 准教授 (80396712) ; OUE Naohide 広島大学, 医歯薬保健学研究院, 准教授 (60346484) ; TOMONAGA Takeshi 独立行政法人医薬基盤研究所, プロジェクトリーダー (80227644) ; OHDAN Hideki 広島大学, 医歯薬保健学研究院, 教授 (10363061)
• Research Collaborator: ADACHI Tomohiro ; SAITO Yasufumi ; MIGUCHI Masashi ; NIITSU Hiroaki
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2016: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2013: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: 大腸癌 / マウスモデル / バイオマーカー / RAS / TGFbetaRII / Kras / TGFbeta / 遺伝子改変マウス / 大腸癌マウスモデル / KRAS変異型大腸癌 / MSI大腸癌マウスモデル

Outline of Final Research Achievements

We applied two types of genomic instability in advanced colon cancer mouse model (colonic epithelial cell specific conditional Apc-knockout mouse) that we established and added another carcinogen driver gene (Kras, TGFβIIR)mutation to Apc mutation to generate complex genetically modified mouse model. The tumor of Apc+Kras mutant mouse was moderately differentiated adenocarcinoma and by comprehensive gene analysis Glut1 and Rcan2 were identified as upregulated and downregluated target genes, respectively. In Apc + TGFβIIRk deficient mice, the expression of GSDMC transcript and protein was elevated. From these mice models, biomarkers useful for treatment such as correlation of genotype-phenotype of oncogenic driver gene and target gene could be identified.

Research Products

• [Journal Article] Choline Deficiency Causes Colonic Type II Natural Killer T (NKT) Cell Loss and Alleviates Murine Colitis under Type I NKT Cell Deficiency. (2017)
  • Author(s): Sagami S, Ueno Y, Tanaka S, Fujita A, Niitsu H, Hayashi R, Hyogo H, Hinoi T, Kitadai Y, Chayama K.
  • Journal Title: PLoS One Volume: 12
  • Peer Reviewed / Open Access
• [Journal Article] KIF11 Is Required for Spheroid Formation by Oesophageal and Colorectal Cancer Cells. (2017)
  • Author(s): Imai T, Oue N, Sentani K, Sakamoto N, Uraoka N, Egi H, Hinoi T, Ohdan H, Yoshida K, Yasui W.
  • Journal Title: Anticancer Res. Volume: 37 Pages: 47-55
  • Peer Reviewed / Open Access
• [Journal Article] Gasdermin C Is Upregulated by Inactivation of Transforming Growth Factor β Receptor Type II in the Presence of Mutated Apc, Promoting Colorectal Cancer Proliferation. (2016)
  • Author(s): Miguchi M, Hinoi T, Shimomura M, Adachi T, Saito Y, Niitsu H, Kochi M, Sada H, Sotomaru Y, Ikenoue T, Shigeyasu K, Tanakaya K, Kitadai Y, Sentani K, Oue N, Yasui W, Ohdan H.
  • Journal Title: PLoS One Volume: 11
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] KRAS mutation leads to decreased expression of regulator of calcineurin 2, resulting in tumor proliferation in colorectal cancer. (2016)
  • Author(s): Niitsu H, Hinoi T, Kawaguchi Y, Sentani K, Yuge R, Kitadai Y, Sotomaru Y, Adachi T, Saito Y, Miguchi M, Kochi M, Sada H, Shimomura M, Oue N, Yasui W, Ohdan H.
  • Journal Title: Oncogenesis. Volume: 5 Issue: 8 Pages: 8-8
  • DOI: 10.1038/oncsis.2016.47
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Increased Calcineurin A Expression Is Associated with a Lower Relapse-Free Survival Rate after Colorectal Cancer Surgery. (2016)
  • Author(s): Niitsu H, Hinoi T, Sentani K, Mukai S, Adachi T, Saito Y, Miguchi M, Kochi M, Sada H, Oue N, Yasui W, Ohdan H.
  • Journal Title: Pathobiology Volume: 83 Issue: 6 Pages: 308-15
  • DOI: 10.1159/000445121
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regulation of multidrug resistance 1 expression by CDX2 in ovarian mucinous adenocarcinoma. (2016)
  • Author(s): Koh I, Hinoi T, Sentani K, Hirata E, Nosaka S, Niitsu H, Miguchi M, Adachi T, Yasui W, Ohdan H, Kudo Y.
  • Journal Title: Cancer Med Volume: 5 Issue: 7 Pages: 1546-55
  • DOI: 10.1002/cam4.697
  • Peer Reviewed / Open Access
• [Journal Article] Mouse model of proximal colon-specific tumorigenesis driven by microsatellite instability-induced Cre-mediated inactivation of Apc and activation of Kras. (2016)
  • Author(s): Kawaguchi Y, Hinoi T, Saito Y, Adachi T, Miguchi M, Niitsu H, Sasada T, Shimomura M, Egi H, Oka S, Tanaka S, Chayama K, Sentani K, Oue N, Yasui W, Ohdan H.
  • Journal Title: J Gastroenterol. Volume: 51 Issue: 5 Pages: 447-457
  • DOI: 10.1007/s00535-015-1121-9
  • Peer Reviewed / Open Access
• [Journal Article] Chlorinated Water Modulates the Development of Colorectal Tumors with Chromosomal Instability and Gut Microbiota in Apc-Deficient Mice. (2015)
  • Author(s): Sasada T, Hinoi T, Saito Y, Adachi T, Takakura Y, Kawaguchi Y, Sotomaru Y, Sentani K, Oue N, Yasui W, Ohdan H.
  • Journal Title: PLoS One. Volume: 10 Issue: 7 Pages: e0132435-e0132435
  • DOI: 10.1371/journal.pone.0132435
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Colonoscopy as a tool for evaluating colorectal tumor development in a mouse model (2014)
  • Author(s): Adachi T, Hinoi T, Sasaki Y, Niitsu H, Saito Y, Miguchi M, Shimomura M, Ohdan H
  • Journal Title: Int J Colorectal Dis Volume: 29 Issue: 2 Pages: 217-223
  • DOI: 10.1007/s00384-013-1791-9
  • Peer Reviewed
• [Presentation] 大腸がんの治療開発に有用な自然発生型大腸がんマウスモデルの確立 (2016)
  • Author(s): 檜井孝夫、安達智洋、斉藤保文、三口真司、新津宏明、河内雅年、下村 学、外丸祐介、仙谷和弘、大上直秀、安井 弥、大段秀樹
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2016-10-08
  • Invited
• [Presentation] 大腸癌自然発生マウスモデルを用いたKRAS変異型大腸癌の遺伝子発現プロファイル解析 (2016)
  • Author(s): 新津宏明、檜井孝夫、川口康夫、仙谷和弘、大上直秀、安達智洋、斉藤保文、三口真司、下村学、安井弥、大段秀樹
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2016-10-08
• [Presentation] The generation and analysis of Transforming growth factor beta receptor II (TGFBR2) mutant colorectal cancer mouse model (2016)
  • Author(s): 三口真司，檜井孝夫，下村学，安達智洋，斎藤保文，新津宏明，伊地知秀明，田中屋宏爾，北台靖彦，仙谷和弘，大上直秀，安井弥，大段秀樹
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2016-10-08
• [Presentation] CDX2P-CreERT2:Apcflox/flox;KrasG12D マウスモデルを用いたタモキシフェン投与量依存性腫瘍発育速度の検討 (2016)
  • Author(s): 佐田春樹、檜井孝夫
  • Organizer: 第75回日本癌学会
  • Place of Presentation: 横浜、日本
  • Year and Date: 2016-10-06
• [Presentation] 消化管癌の発生・病態におけるCDX2の機能解析とそれを応用した大腸癌マウスモデルの確立 (2016)
  • Author(s): 檜井孝夫、安達智洋、斉藤保文、三口真司、河内雅年、佐田春樹、仙谷和弘、大上直秀、安井弥、大段秀樹
  • Organizer: 第47回日本臨床分子形態学会総会・学術集会
  • Place of Presentation: 長崎
  • Year and Date: 2016-09-18
  • Invited
• [Presentation] CDX2P-CreERT2:Apcflox/flox;KrasG12D マウスモデルを用いた大腸癌発生速度の検討 (2016)
  • Author(s): 河内雅年, 檜井孝夫, 安達智洋, 斎藤保文, 三口真司, 新津宏明, 佐田春樹, 坂本直也, 仙谷和弘, 大上直秀, 安井弥, 大段秀樹
  • Organizer: 第27回日本消化器癌発生学会
  • Place of Presentation: 鹿児島
  • Year and Date: 2016-09-15
• [Presentation] Establishment of novel conditional Apc-knockout colorectal cancer mouse models with distinct genomic stability and its application to clinical diagnosis and therapy. (2016)
  • Author(s): Takao HINOI, Eric R. FEARON, Wataru YASUI, Hideki OHDAN
  • Organizer: K-INT
  • Place of Presentation: Kure, Japan
  • Year and Date: 2016-07-21
  • Int'l Joint Research / Invited
• [Presentation] ２つのドライバー遺伝子による複合的遺伝子改変によるマウス大腸癌モデルの確立とその臨床応用 (2016)
  • Author(s): 檜井孝夫、安達智洋、斉藤保文、三口真司、新津宏明、河内雅年、下村 学、石崎康代、惠木裕之、大段秀樹
  • Organizer: 第70回日本消化器外科学会総会
  • Place of Presentation: 浜松市
  • Year and Date: 2016-07-15
• [Presentation] The generation of colorectal cancer mouse model based on microsatellite instability and the identification of transforming growth factor-beta signal target (2015)
  • Author(s): Masashi Miguchi, Takao Hinoi, Manabu Shimomura, Tomohiro Adachi, Yasufumi Saito, Hiroaki Niitsu, Masatoshi Kochi, Yusuke Sotomaru, Hideaki Ijichi, Tsuneo Ikenoue, Kunitoshi Shigeyasu, Kohji Tanakaya, Kazuhiro Sentani, Naohide Oue, Wataru Yasui, Hideki Ohdan
  • Organizer: AACR 2015
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-18 – 2015-04-22
• [Presentation] Impact of synbiotics administration on tumorigenesis of colon cancer mouse model (2015)
  • Author(s): Yasufumi Saito, Takao Hinoi, Tomohiro Adachi, Manabu Shimomura, Masashi Miguchi, Hiroaki Niitsu, Masatishi Kochi, Hideki Ohdan, Kazuhiro Sentani, Naohide Oue, Wataru Yasui
  • Organizer: AACR 2015
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-18 – 2015-04-22
• [Presentation] Gene expression profiling for oncogenic Kras mutation in mice and human colorectal cancer (2015)
  • Author(s): Hiroaki Niitsu, Takao Hinoi, Yasuo Kawaguchi, Kazuhiro Sentani, Naohide Oue, Yusuke Sotomaru, Tomohiro Adachi, Yasufumi Saito, Masashi Miguchi, Masatoshi Kochi, Manabu Shimomura, Wataru Yasui, and Hideki Ohdan
  • Organizer: AACR 2015
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-18 – 2015-04-22
• [Presentation] 左側結腸癌モデル(CPC;Apc)マウスを使用した大腸癌発育浸潤因子の同定と臨床応用にむけて (2014)
  • Author(s): 安達智洋、檜井孝夫、齊藤保文、佐々田達成、川口康夫、下村学、三口真司、新津宏明、大段秀樹
  • Organizer: 日本消化器癌発生学会
  • Place of Presentation: 福岡、日本
  • Year and Date: 2014-11-13 – 2014-11-14
• [Presentation] Impact of Synbiotics administration on tumorigenesis of colon cancer mouse model (2014)
  • Author(s): 斉藤保文 檜井孝夫 恵木浩之 下村学 安達智洋 三口真司 新津宏明 澤田紘幸 河内雅年 大上直秀 安井弥 大段秀樹
  • Organizer: 第25回消化器癌発生学会
  • Place of Presentation: 福岡、日本
  • Year and Date: 2014-11-11 – 2014-11-14
• [Presentation] Sulindac delayed and suppressed the tumor progression, was not effective on inhibition of tumor initiation in a human colorectal cancer mouse model (CPC;Apc mouse). (2014)
  • Author(s): Tomohiro Adachi, Takao Hinoi, Naohide Oue, Yusuke Sotomaru,Yasufumi Saito, Masashi Miguchi,Hiroaki Niitsu, Masatoshi Kochi, Manabu Shimomura, Wataru Yasui, and Hideki Ohdan
  • Organizer: AACR 2014
  • Place of Presentation: SanDiego, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] 大腸癌自然発生マウスモデルの腫瘍発生における飲用水中塩素濃度の影響 (2014)
  • Author(s): 齊藤保文、檜井孝夫、佐々田達成、川口康夫、下村学、安達智洋、三口真司、新津宏明、大段秀樹
  • Organizer: 第114回日本外科学会
  • Place of Presentation: 京都、日本
  • Year and Date: 2014-04-03 – 2014-04-05
• [Presentation] 左側結腸癌マウス（CPC;Apc)モデルのDSS単独投与による発癌の影響について (2014)
  • Author(s): 安達智洋、檜井孝夫、齊藤保文、佐々田達成、川口康夫、下村学、三口真司、新津宏明、大段秀樹
  • Organizer: 第114回日本外科学会
  • Place of Presentation: 京都、日本
  • Year and Date: 2014-04-03 – 2014-04-05
• [Presentation] Sulindac delayed and suppressed the tumor progression, was not effective on inhibition of tumor initiation in a human colorectal cancer mouse model (CPC;Apc mouse)
  • Author(s): Tomohiro Adachi, Takao Hinoi, Yuu Sasaki, Manabu Shimomura, Yasufumi Saito, Masashi Miguchi, Hiroaki Niitsu, Yuusuke Sotomaru, Naohide Oue, Wataru Yasui, Hideki Ohdan
  • Organizer: American Association for Cancer Research Annual Meeting 2014
  • Place of Presentation: San Diego, CA, USA
• [Book] 診療ガイドライン UP-TO-DATE 2016-2017 (2016)
  • Author(s): 檜井孝夫 (監修 門脇 孝 他）
  • Total Pages: 968
  • Publisher: メディカルレビュー社