Elucidation of mechanisms underlying colorectal tumorigenesis associated with deregulation of new Wnt targets

• Project/Area Number: 17H03575
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: The University of Tokyo
• Principal Investigator: Furukawa Yoichi 東京大学, 医科学研究所, 教授 (20272560)
• Co-Investigator(Kenkyū-buntansha): 山口 貴世志 東京大学, 医科学研究所, 特任講師 (50466843) ; 池上 恒雄 東京大学, 医科学研究所, 准教授 (80396712)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2018: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2017: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: がん / シグナル伝達 / Wnt

Outline of Final Research Achievements

In this study, we identified new target genes regulated by the canonical Wnt signaling. Among the genes, FRMD5 was positively regulated, and IFIT2 was negatively regulated by the signaling. Elevated expression of FRMD5 is associated with invasion of colorectal cancer (CRC) cells, and high FRMD5 expression in CRC tissues is linked to poor prognosis. On the other hand, reduced IFIT2 expression is associated with cell proliferation and resistance to apoptosis. Furthermore, we identified IRF1 as a transcriptional regulator of IFIT2. Importantly, we revealed that activation of the Wnt signaling downregulates IRF1 through its destabilization, and that a deubiquitinating enzyme USP1 plays an important role in the stabilization of IRF1. We also found that UAF1, a USP-interacting protein, is reduced by the activated Wnt signaling. These data suggest that activation of the signaling reduces the stability of IRF1 through its ubiquitination by suppression of USP1-UAF1 activity.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は大腸がん発生・進展メカニズムの理解に役立つのみならず、新たなバイオマーカーや治療薬開発などに応用できるかもしれない。学術面では、Wnt活性化により特定のタンパク質分解が誘導されるという発見は、これまで知られていない新たなWntシグナル制御機構で、他にも制御される分子が存在する可能性が考えられる。社会的意義ではFRMD5の発現と臨床情報の詳細な検討により、FRMD5が新規予後マーカーとして利用できる可能性が示された。またWnt阻害によって発現が増加するIFIT2やIRF1は、Wntを阻害する化合物、抗体等の探索プローブとしての応用が可能であり、今後の治療薬開発に役立つかもしれない。

Research Products

• [Journal Article] Development of an MSI-positive colon tumor with aberrant DNA methylation in a PPAP patient (2019)
  • Author(s): Yamaguchi K, Shimizu E, Yamaguchi R, Imoto S, Komura M, Hatakeyama S, Noguchi R, Takane K, Ikenoue T, Gohda Y, Yano H, Miyano S, Furukawa Y
  • Journal Title: J Hum Genet. Volume: 64(8) Issue: 8 Pages: 729-740
  • DOI: 10.1038/s10038-019-0611-7
  • Peer Reviewed / Open Access
• [Journal Article] Importance of Gastric Cancer for the Diagnosis and Surveillance of Japanese Lynch Syndrome Patients (2019)
  • Author(s): Ikenoue T, Arai M, Ishioka C, Iwama T, Kaneko S, Matsubara N, Moriya Y, Nomizu T, Sugano K, Tamura K, Tomita N, Yoshida T, Sugihara K, Naruse H, Yamaguchi K, Nojima M, Nakamura Y, Furukawa Y; Japanese society for cancer of the colon and rectum (JSCCR)
  • Journal Title: J Hum Genet. Volume: 64 Issue: 12 Pages: 1187-1194
  • DOI: 10.1038/s10038-019-0674-5
  • Peer Reviewed / Open Access
• [Journal Article] Deep sequencing across germline GWAS signals relating to breast cancer events in women receiving aromatase inhibitors for adjuvant therapy of early breast cancer. (2019)
  • Author(s): Ingle JN, Kalari KR, Momozawa Y, Kubo M, Furukawa Y, Shepherd LE, Ellis MJ, Goss PE, Barman P, Carlson EE, Sinnwell JP, Tang X, Goetz MP, Chen BE, Cairns J, Weinshilboum RM, Wang L
  • Journal Title: Pharmacogenetics and Genomics Volume: 29(8) Issue: 8 Pages: 183-191
  • DOI: 10.1097/fpc.0000000000000382
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/β-catenin signaling in colorectal cancer cells (2019)
  • Author(s): Ohsugi T, Yamaguchi K, Zhu C, Ikenoue T, Takane K, Shinozaki M, Tsurita G, Yano H, Furukawa Y
  • Journal Title: Oncogene Volume: 38(32) Issue: 32 Pages: 6051-6064
  • DOI: 10.1038/s41388-019-0856-9
  • Peer Reviewed
• [Journal Article] Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/β-catenin signaling in colorectal cancer cells (2019)
  • Author(s): Ohsugi T, Yamaguchi K, Zhu C, Ikenoue T, Takane K, Shinozaki M, Tsurita G, Yano H, Furukawa Y.
  • Journal Title: Oncogene Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Development of an MSI-positive colon tumor with aberrant DNA methylation in a PPAP patient (2019)
  • Author(s): Yamaguch K, Shimizu E, Yamaguchi R, Imoto S, Komura M, Hatakeyama S, Noguchi R, Takane K, Ikenoue T, Gohda Y, Yano H, Miyano S, Furukawa Y.
  • Journal Title: Journal of Human Genetics Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Efficacy of liquid-based genetic diagnosis of endometrial cancer. (2018)
  • Author(s): Matsuura M, Yamaguchi K, Tamate M, Satohisa S, Teramoto M, Iwasaki M, Sugita S, Hasegawa T, Koubo R, Takane K, Ikenoue T, Furukawa Y, Saito T.
  • Journal Title: Cancer Science Volume: 109 Issue: 12 Pages: 4025-4032
  • DOI: 10.1111/cas.13819
  • Peer Reviewed / Open Access
• [Journal Article] Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer. (2018)
  • Author(s): Johmura Y, Maeda I, Suzuki N, Wu W, Goda A,Morita M, Yamaguchi K, Yamamoto M, Nagasawa S, Kojima Y, Tsugawa K, Inoue N, Miyoshi Y, Osako T Akiyama F, Maruyama R, Inoue JI, Fukukawa Y, Ohta T, Nkanishi M.
  • Journal Title: J Clin Invest. Volume: 128 Issue: 12 Pages: 5603-5619
  • DOI: 10.1172/jci121679
  • Peer Reviewed / Open Access
• [Journal Article] Genetic variation determines VEGF-A plasma levels in cancer patients. (2018)
  • Author(s): Innocenti F, Jiang C, Sibley AB, Etheridge AS, Hatch AJ, Denning S, Niedzwiecki D, Shterev ID, Lin J, Furukawa Y, Kubo M, Kindler HL, Auman JT, Venook AP, Hurwitz HI, McLeod HL, Ratain MJ, Gordan R, Nixon AB, Owzar K.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 16332-16332
  • DOI: 10.1038/s41598-018-34506-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Germline genome-wide association studies in women receiving neoadjuvant chemotherapy with or without bevacizumab. (2018)
  • Author(s): Ingle JN, Kalari KR, Wickerham DL, von Minckwitz G, Fasching PA, Furukawa Y, Mushiroda T, Goetz MP, Barman P, Carlson EE, Rastogi P, Costantino JP, Cairns J, Paik S, Bear HD, Kubo M, Wang L, Wolmark N, Weinshilboum RM.
  • Journal Title: Pharmacogenet Genomics Volume: 28 Issue: 6 Pages: 147-152
  • DOI: 10.1097/fpc.0000000000000337
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] FERM domain-containing protein 5 (FRMD5) as a novel target of β-catenin/TCF7L2 complex. (2017)
  • Author(s): Zhu C, Yamaguchi K, Osugi T, Terakado Y, Noguchi R, Ikenoue T, Furukawa Y
  • Journal Title: Cancer Science Volume: 印刷中 Issue: 4 Pages: 612-619
  • DOI: 10.1111/cas.13174
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Decreased expression of interferon-induced protein 2 (IFIT2) by Wnt/β-catenin signaling confers anti-apoptotic properties to colorectal cancer cells. (2017)
  • Author(s): Ohsugi T, Yamaguchi K, Zhu C, Ikenoue T, Furukawa Y.
  • Journal Title: Oncotarget Volume: 8 Issue: 59 Pages: 100176-100186
  • DOI: 10.18632/oncotarget.22122
  • Peer Reviewed / Open Access
• [Journal Article] Bidirectional reporter assay using HAL promoter and TOPFLASH improves specificity in high-throughput screening of Wnt inhibitors. (2017)
  • Author(s): Yamaguchi K, Zhu C, Ohsugi T, Yamaguchi Y, Ikenoue T, Furukawa Y.
  • Journal Title: Biotechnology and Bioengineering Volume: 114 Issue: 12 Pages: 2868-2882
  • DOI: 10.1002/bit.26394
  • Peer Reviewed / Open Access
• [Journal Article] Requirement of glycosylation machinery in TLR responses revealed by CRISPR/Cas9 screening (2017)
  • Author(s): Sato Ryota、Shibata Takuma、Tanaka Yu、Kato Chiharu、Yamaguchi Kiyoshi、Furukawa Yoichi、Shimizu Eigo、Yamaguchi Rui、Imoto Seiya、Miyano Satoru、Miyake Kensuke
  • Journal Title: International Immunology Volume: 29 Issue: 8 Pages: 347-355
  • DOI: 10.1093/intimm/dxx044
  • Peer Reviewed / Open Access
• [Presentation] ロングリードシーケンスによるリンチ症候群患者のミスマッチ修復遺伝子の構造異常の解析 (2019)
  • Author(s): 山口 貴世志, 笠島 理加, 清水 英悟, 高根 希世子, 池上 恒雄, 山口 類, 井元 清哉, 宮野 悟, 古川 洋一
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 大腸癌においてWnt /β-カテニンシグナルはインターフェロン制御因子 (2019)
  • Author(s): 大杉友之, 山口貴世志, 池上恒雄, 高根希世子, 篠崎大, 矢野秀朗, 釣田義一郎, 古川洋一
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] The CRISPR/Cas9-mediated gene knockout screening to analyze EMT-MET plasticity in triple-negative breast cancer. (2019)
  • Author(s): Mizuki Yamamoto, Kiyoshi Yamaguchi, Yoichi Furukawa, Jun-ichiro Inoue.
  • Organizer: Cell Symposia
  • Int'l Joint Research
• [Presentation] Whole-exome sequencing of high-grade fetal lung adenocarcinomas (2019)
  • Author(s): Masaki Suzuki, Rika Kasajima, Tomoyuki Yokose, Rui Yamaguchi, Seiya Imoto, Yoichi Furukawa, Satoru Miyano3 Emi Yoshioka, Kota Washimi, Yoichiro Okubo, Kae Kawachi, Yohei Miyagi
  • Organizer: The 16th Korean-Japanese Conjoint Slide Conference of International Academy of Pathology
  • Int'l Joint Research
• [Presentation] Wnt/β-catenin signaling controls interferon regulatory factor 1 (IRF1) in colorectal cancer cells. (2019)
  • Author(s): Yamaguchi K, Ohsugi T, Takane K, Ikenoue T, Furukawa Y
  • Organizer: 11th AACR-JCA Joint Conference
  • Int'l Joint Research
• [Presentation] Genetic analysis of pseudomyxoma peritonei (2018)
  • Author(s): Furukawa Y
  • Organizer: The 9th Asian Pacific Topic Conference
  • Int'l Joint Research / Invited
• [Presentation] Molecular features of colorectal cancer in patient with polymerase proofreading-associated polyposis (PPAP) (2018)
  • Author(s): Yamaguchi K, Shimizu E, Hatakeyama S, Noguchi R, Ikenoue T, Yamaguchi R, Imoto S, Miyano S, Furukawa Y
  • Organizer: The Joint Symposium of the 13th International Symposium of the Institute Network for Biomedical Sciences and the 28th Hot Spring Harbor International Symposium 2018
  • Int'l Joint Research
• [Presentation] Identification of FERM Domain-Containing Protein 5 (FRMD5) as a Novel Target of β-Catenin/TCF7L2 Complex (2017)
  • Author(s): Furukawa Y, Zhu C, Ohsugi T, Terakado Y, Noguchi R, Ikenoue T, Yamaguchi K
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] Wnt Signaling Induces Anti-Apoptotic Effect in Colorectal Cancer Cells Through the Suppression of IFIT (2017)
  • Author(s): Ohsugi T, Zhu C, Ohsugi T, Terakado Y, Noguchi R, Ikenoue T, Yamaguchi K, Furukawa Y
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] 人工知能を用いた臨床シークエンスの取り組み (2017)
  • Author(s): 古川洋一
  • Organizer: 第15回日本臨床腫瘍学会学術集会
  • Invited
• [Presentation] ゲノム情報を用いた治療薬開発・治療法選択 (2017)
  • Author(s): 古川洋一
  • Organizer: 第26回日本癌病態治療研究会
  • Invited
• [Presentation] 臨床シークエンスにおける人工知能を用いた精密医療開発 (2017)
  • Author(s): 古川洋一
  • Organizer: 第59回日本小児血液・がん学会学術集会
  • Invited
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/furukawa/research/
• [Remarks] 東京大学医科学研究所臨床ゲノム腫瘍学分野古川洋一研究室
  • URL: http://www.ims.u-tokyo.ac.jp/furukawa/research/
• [Remarks] 東京大学医科学研究所 臨床ゲノム腫瘍学分野 ホームページ
  • URL: http://www.ims.u-tokyo.ac.jp/furukawa/index.html