p53制御経路の網羅的解析による腫瘍細胞の特性の解明と治療法の開発

• Project Area: Conquering cancer through neo-dimensional systems understanding
• Project/Area Number: 16H01566
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: The University of Tokyo
• Principal Investigator: 松田 浩一 東京大学, 大学院新領域創成科学研究科, 教授 (90401257)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000); Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: p53 / 癌 / がん / CRISPR/CAS9 / ゲノム解析

Outline of Annual Research Achievements

癌抑制遺伝子p53はヒト癌の約半数で変異が認められ発ガン過程において最も重要な遺伝子です。殆どの癌で転写因子としてのp53の機能が失活することから、p53変異細胞の特性を明らかにすることで、癌細胞が共通して持つ特徴、がんのアキレス腱を知ることが可能となる。本研究によって、p53変異細胞の特性を明らかとすることによって、癌細胞に普遍的に効果を示す治療法の開発を最終的な目標である。
我々はこれまでp53によって発現誘導される遺伝子群の解析を継続して実施し、p53を介した癌化抑制機構の解明を進めてきた。今回マウス24臓器における網羅的遺伝子解析の結果、p53によって5000以上の遺伝子が制御されることを明らかとした(Ebiomedicine 2017, oncotarget 2017)。さらにゲノム編集技術によるp53活性型マウスの作成と遺伝子発現解析、CRISPR/CAS9ライブラリーを用いた合成致死遺伝子のスクリーニング及びヒトがん組織、細胞株の発現情報データなどの統合的解析を実施した。これらの研究によって、p53を介したアミノ酸代謝制御(Sci. Adv. 2017)、アポトーシス(Neoplasia2017)、転移浸潤(Oncotarget2017, IJO 2017)や免疫応答制御(Sci Rep. 2017)などの発がん抑制メカニズムを明らかとした。さらにCRISPR/CAS9によるgRNAライブラリースクリーニングによるp53と合成致死に働く経路の同定及びp53によるマイクロバイオーム制御機構も明らかとした。これらの研究成果は、p53による遺伝子制御機構の全貌の解明及び新規治療法の開発につながると期待される。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Deep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese (2018)
  • Author(s): Okada Yukinori、Momozawa Yukihide、Sakaue Saori、Kanai Masahiro、Ishigaki Kazuyoshi、Akiyama Masato、Kishikawa Toshihiro、Arai Yasumichi、Sasaki Takashi、Kosaki Kenjiro、Suematsu Makoto、Matsuda Koichi、Yamamoto Kazuhiko、Kubo Michiaki、Hirose Nobuyoshi、Kamatani Yoichiro
  • Journal Title: Nature Communications Volume: 9 Pages: 1631-1631
  • DOI: 10.1038/s41467-018-03274-0
  • Peer Reviewed / Open Access
• [Journal Article] Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes (2018)
  • Author(s): Low SK, Takahashi A, Ebana Y, Ozaki K, Christophersen IE, Ellinor PT; AFGen Consortium, Ogishima S, Yamamoto M, Satoh M, Sasaki M, Yamaji T, Iwasaki M, Tsugane S, Tanaka K, Naito M, Wakai K, Tanaka H, Furukawa T, Kubo M, Ito K, Kamatani Y, Tanaka T.、ほか
  • Journal Title: Nat Genet Volume: 49 Pages: 524-537
  • DOI: 10.1038/s41588-018-0058-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GWAS identifies two novel colorectal cancer loci at 16q24.1 and 20q13.12. (2018)
  • Author(s): Tanikawa C, Kamatani Y, Takahashi A, Nagayama S, Mimori K, Mori M, Yasuda J, Tsuboi A, Shimizu A, Sasaki M, Yamaji T, Tsugane S, Naito M, Wakai K, Koyama T, Takezaki T, Yuji K, Murakami Y, Nakamura Y, Matsuda K, et al.
  • Journal Title: Carcinogenesis Volume: Epub Pages: 652-660
  • DOI: 10.1093/carcin/bgy026
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association study identifies seven novel susceptibility loei for primary open-angle glaucoma (2018)
  • Author(s): Shiga Y, Akiyama M, Nishiguchi K M, Sato K, Shimozawa N, Takahashi A, Momozawa Y, Hirata M, Matsuda K, Yamaji T, Iwasaki M, Tsugane S, Oze I, Mikami H, Naito M, Wakai K, Yoshikawa M, Miyake M, Yanaka T, et al.
  • Journal Title: Human Molecular Genetics Volume: 27 Issue: 8 Pages: 1458-1467
  • DOI: 10.1093/hmg/ddy053
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Citrullination of RGG motifs in FET proteins by PAD4 regulates protein aggregation and ALS susceptibility (2018)
  • Author(s): Tanikawa Chizu、Ueda Koji、Suzuki Akari、Iida Aritoshi、Nakamura Ryoichi、Atsuta Naoki、Tohnai Genki、Sobue Gen、Saichi Naomi、Momozawa Yukihide、Kamatani Yoichiro、Kubo Michiaki、Yamamoto Kazuhiko、Nakamura Yusuke、Matsuda Koichi
  • Journal Title: Cell reports Volume: 22 Pages: 1473-1483
  • DOI: 10.1016/j.celrep.2018.01.031
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases (2018)
  • Author(s): Kanai M, Akiyama M, Takahashi A, Matoba N, Momozawa Y, Ikeda M, Iwata N, Ikegawa S, Hirata M, Matsuda K, Kubo M, Okada Y, Kamatani Y
  • Journal Title: Nature Genetics Volume: 50 Pages: 390-400
  • DOI: 10.1038/s41588-018-0047-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Decrease in PSCA expression caused by helicobacter pylori infection may promote progression to severe gastritis (2017)
  • Author(s): Toyoshima O, Tanikawa C, Yamamoto R, Watanabe H, Yamashita H, Sakitani K, Yoshida S, Kubo M, Matsuo K, Ito H, Koike K, Seto Y, Matsuda K.
  • Journal Title: Oncotarget Volume: 9 Issue: 3 Pages: 3936-3945
  • DOI: 10.18632/oncotarget.23278
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a p53-repressed gene module in breast cancer cells (2017)
  • Author(s): Miyamoto T, Tanikawa C, Yodsurang V, Zhang YZ, Imoto S, Yamaguchi R, Miyano S, Nakagawa H, Matsuda K
  • Journal Title: Oncotarget Volume: 8(34) Pages: 55821-55836
  • DOI: 10.18632/oncotarget.19608
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of a novel p53 target, COL17A1, that inhibits breast cancer cell migration and invasion (2017)
  • Author(s): Yodsurang Varalee、Tanikawa Chizu、Miyamoto Takafumi、Lo Paulisally Hau Yi、Hirata Makoto、Matsuda Koichi
  • Journal Title: Oncotarget Volume: 8 Pages: 55790-55803
  • DOI: 10.18632/oncotarget.18433
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association study identifies 112 new loci for body mass index in the Japanese population. (2017)
  • Author(s): Akiyama M, Okada Y, Kanai M, Takahashi A, Momozawa Y, Ikeda M, Iwata N, Ikegawa S, Hirata M, Matsuda K, Iwasaki M, Yamaji T, Sawada N, Hachiya T, Tanno K, Shimizu A, Hozawa A, Minegishi N, Tsugane S, Yamamoto M, Kubo M and Kamatani Y
  • Journal Title: Nature Genetics Volume: 49 Pages: 1458-1462
  • DOI: 10.1038/ng.3951
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a p53 target, CD137L, that mediates growth suppression and immune response of osteosarcoma cells (2017)
  • Author(s): Yusuke Tsuda, Chizu Tanikawa, Takafumi Miyamoto, Makoto Hirata, Varalee Yodsurang, Yao-zhong Zhang, Seiya Imoto, Rui Yamaguchi, Satoru Miyano, Hiroshi Takayanagi, Hirotaka Kawano, Hidewaki Nakagawa, Sakae Tanaka, and Koichi Matsuda
  • Journal Title: Scientific Reports Volume: 7(1) Pages: 10739-10739
  • DOI: 10.1038/s41598-017-11208-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of tubular recycling endosome biogenesis by the p53-MICALL1 pathway (2017)
  • Author(s): Takahashi Yukie、Tanikawa Chizu、Miyamoto Takafumi、Hirata Makoto、Wang Guanxiong、Ueda Koji、Komatsu Tsunehiko、Matsuda Koichi
  • Journal Title: Int J Oncol. Volume: 51 Pages: 724-736
  • DOI: 10.3892/ijo.2017.4060
  • Peer Reviewed
• [Journal Article] Argininosuccinate synthase 1 is an intrinsic Akt repressor transactivated by p53 (2017)
  • Author(s): Miyamoto Takafumi、Lo Paulisally Hau Yi、Saichi Naomi、Ueda Koji、Hirata Makoto、Tanikawa Chizu、Matsuda Koichi
  • Journal Title: Sci Adv Volume: 3 Pages: 1603204-1603204
  • DOI: 10.1126/sciadv.1603204
  • Peer Reviewed / Open Access
• [Journal Article] The Transcriptional Landscape of p53 Signalling Pathway (2017)
  • Author(s): Tanikawa C, Zhang YZ, Yamamoto R, Tsuda Y, Tanaka M, Funauchi Y, Mori J, Imoto S, Yamaguchi R, Nakamura Y, Miyano S, Nakagawa H, Matsuda K
  • Journal Title: EBioMedicine Volume: 20 Pages: 109-119
  • DOI: 10.1016/j.ebiom.2017.05.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism (2017)
  • Author(s): Sapkota Y, Steinthorsdottir V, Morris AP, et al.
  • Journal Title: Nature Communications Volume: 8 Pages: 15539-15539
  • DOI: 10.1038/ncomms15539
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EPSIN 3, A Novel p53 Target, Regulates the Apoptotic Pathway and Gastric Carcinogenesis (2017)
  • Author(s): Mori J, Tanikawa C, Ohnishi N, Funauchi Y, Toyoshima O, Ueda K, Matsuda K.
  • Journal Title: Neoplasia. Volume: 19 Pages: 185-195
  • DOI: 10.1016/j.neo.2016.12.010
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Overview of BioBank Japan follow-up data in 32 diseases (2017)
  • Author(s): Hirata M, Nagai A, Kamatani Y, Ninomiya T, Tamakoshi A, Yamagata Z, Kubo M, Muto K, Kiyohara Y, Mushiroda T, Murakami Y, Yuji K, Furukawa Y, Zembutsu H, Tanaka T, Ohnishi Y, Nakamura Y; BioBank Japan Cooperative Hospital Group., Matsuda K.
  • Journal Title: J Epidemiol. Volume: 27 Issue: Supplement_III Pages: S22-S28
  • DOI: 10.1016/j.je.2016.12.006
  • Peer Reviewed
• [Journal Article] Cross-sectional analysis of BioBank Japan clinical data: A large cohort of 200,000 patients with 47 common diseases (2017)
  • Author(s): Hirata M, Kamatani Y, Nagai A, Kiyohara Y, Ninomiya T, Tamakoshi A, Yamagata Z, Kubo M, Muto K, Mushiroda T, Murakami Y, Yuji K, Furukawa Y, Zembutsu H, Tanaka T, Ohnishi Y, Nakamura Y; BioBank Japan Cooperative Hospital Group., Matsuda K.
  • Journal Title: J Epidemiol. Volume: 27 Issue: Supplement_III Pages: S9-S21
  • DOI: 10.1016/j.je.2016.12.003
• [Journal Article] Regulation of myo-inositol biosynthesis by p53-ISYNA1 pathway. (2016)
  • Author(s): Tomoyuki Koguchi, Chizu Tanikawa, Jinichi Mori, Yoshiyuki Kojima, Koichi Matsuda
  • Journal Title: Int J Oncol. Volume: 印刷中 Pages: 2415-24
  • DOI: 10.3892/ijo.2016.3456
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Multi-Omics analysis of tumor suppressor p53 signaling pathway (2018)
  • Author(s): Koichi Matsuda
  • Organizer: Program IARI symposium CRCL
  • Int'l Joint Research / Invited
• [Presentation] Cancer susceptible germline variants and their applications for precision medicine (2017)
  • Author(s): Koichi Matsuda
  • Organizer: The 1st International Conference for Precision Cancer Medicine（ICPC2017）
  • Int'l Joint Research / Invited
• [Presentation] Identification of p53 downstream pathway by multiomics analysis (2017)
  • Author(s): Koichi Matsuda,Chizu Tanikawa
  • Organizer: 17th International p53 Workshop
  • Int'l Joint Research
• [Presentation] がんのゲノム医療実現に向けて:ゲノム解析による 疾患発症メカニズムの解明と 個別化医療 (2017)
  • Author(s): Koichi Matsuda
  • Organizer: 第14回 Tokyo Metropolitan Kidney Cancer Meeting
  • Invited
• [Presentation] From cancer etiology by molecular epidemiological techniques to cancer prevention research (2017)
  • Author(s): Koichi Matsuda
  • Organizer: 第76回 日本癌学会学術総会
  • Invited
• [Presentation] Identification of a p53-repressed gene module in breast cancer cells (2017)
  • Author(s): Takafumi Miyamoto , Chizu Tanikawa , Seiya Imoto , Rui Yamaguchi , Satoru Miyano , Hidewaki Nakagawa5 , Koichi Matsuda
  • Organizer: 第76会日本癌学会学術総会
• [Presentation] Identification of a novel p53 target, COL17A1, that inhibits breast cancer cell migration and invasion (2017)
  • Author(s): Varalee Yodsurang , Chizu Tanikawa , Makoto Hirata , Takafumi Miyamoto , Yao-zhong Zhang , Satoru Miyano , Seiya Imoto , Rui Yamaguchi , Hidewaki Nakagawa , Yusuke Nakamura , Koichi Matsuda
  • Organizer: 第76会日本癌学会学術総会
• [Presentation] The transcriptional landscape of p53 signalling pathway (2017)
  • Author(s): Chizu Tanikawa , Yao-zhong Zhang , Seiya Imoto , Rui Yamaguchi , Yusuke Nakamura , Satoru Miyano , Hidewaki Nakagawa , Koichi Matsuda
  • Organizer: 第76会日本癌学会学術総会
• [Presentation] Establishment of BioBank Japan searching system for biospecimen, based on clinical information database (2017)
  • Author(s): Makoto Hirata , Seiya Imoto , Yoichi Furukawa , Yoshinori Murakami , Koichi Matsuda
  • Organizer: 第76会日本癌学会学術総会
• [Presentation] Current progress in cancer genomics and genetics (2016)
  • Author(s): Koichi Matsuda
  • Organizer: The 75th Annual meeting of the Japanese cancer association
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Invited
• [Presentation] 次世代ＤＮＡシークエンスによるがんの個別化医療の可能性 (2016)
  • Author(s): 松田浩一
  • Organizer: 癌治療学会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Invited