Analysis of pathogenic mechanisms of IPMN using GNAS gene modified mousepathogenic mechanisms

• Project/Area Number: 16K09398
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Hyogo Medical University
• Principal Investigator: OHMURAYA Masaki 兵庫医科大学, 医学部, 教授 (60398229)
• Co-Investigator(Kenkyū-buntansha): 古川 徹 東北大学, 医学系研究科, 教授 (30282122)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: IPMN / RNF43 / 膵管内乳頭粘液性腫瘍 / GNAS / 遺伝子改変マウス / GNAS遺伝子 / RNF43遺伝子 / Kras / アポトーシス

Outline of Final Research Achievements

In this research project, RNF43 gene knockout mice were generated and analyzed. RNF43 encodes an E3 ubiquitin ligase and negatively regulates Wnt signaling. RNF43 KO mice were born according to Mendelian frequency, and there was no difference in their growth as compared to wild. As RNF43 somatic mutations of RNF43 are found in 18% or more of colon cancer and endometrial cancer (Nat Genet, 2014), azoxymethane (AOM) and DSS were administered to mice (AOM / DSS mice) As a result of examining whether there is a difference in cancer carcinogenesis, it was found that the tumor was large and that RNF43 had the function of suppressing the progression of colorectal cancer.

Academic Significance and Societal Importance of the Research Achievements

IPMNではKRAS、GNAS、RNF43遺伝子の変異が重複して見られる。今回はRNF43に関して、そのノックアウトマウスを作製し、単独欠損では膵臓に異常を来さないこと、また大腸発がんモデルを用いると、やはりRNF43が腫瘍発生に抑制的に働いていることが明らかとなった。今後はIPMNに関してもその分子メカニズムを解明することで、新たな治療法の開発につながると予想される。

Research Products

• [Journal Article] Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas (2019)
  • Author(s): Arima Kota、Ohmuraya Masaki、Miyake Keisuke、Koiwa Mayu、Uchihara Tomoyuki、Izumi Daisuke、Gao Feng、Yonemura Atsuko、Bu Luke、Okabe Hirohisa、Imai Katsunori、Hashimoto Daisuke、Baba Yoshifumi、Chikamoto Akira、Yamashita Yo-ichi、Furukawa Toru、Araki Kimi、Baba Hideo、Ishimoto Takatsugu
  • Journal Title: Oncogene. Volume: 38 Pages: 1211-1224
  • DOI: 10.1038/s41388-018-0510-y
  • Peer Reviewed
• [Journal Article] Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression (2018)
  • Author(s): Eto T, Miyake K, Nosho K, Ohmuraya M, Imamura Y, Arima K, Kanno S, Fu L, Kiyozumi Y, Izumi D, Sugihara H, Hiyoshi Y, Miyamoto Y, Sawayama H, Iwatsuki M, Baba Y, Yoshida N, Furukawa T, Araki K, Baba H, Ishimoto T
  • Journal Title: J Pathol. Volume: 245 Pages: 445-455
  • DOI: 10.1002/path.5098
  • Peer Reviewed
• [Journal Article] Differential expression of Lutheran/BCAM regulates biliary tissue remodeling in ductular reaction during liver regeneration (2018)
  • Author(s): Miura Yasushi、Matsui Satoshi、Miyata Naoko、Harada Kenichi、Kikkawa Yamato、Ohmuraya Masaki、Araki Kimi、Tsurusaki Shinya、Okochi Hitoshi、Goda Nobuhito、Miyajima Atsushi、Tanaka Minoru
  • Journal Title: Elife. Volume: 7 Pages: 36572-36572
  • DOI: 10.7554/elife.36572
  • Peer Reviewed / Open Access
• [Journal Article] Generation of and characterization of anti-IL-11 antibodies using newly established Il11-deficient mice. (2018)
  • Author(s): Deguchi Y, Nishina T, Asano K, Ohmuraya M, Nakagawa Y, Nakagata N, Sakuma T, Yamamoto T, Araki K, Mikami T, Tanaka M, Nakano H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 505 Pages: 453-459
  • DOI: 10.1016/j.bbrc.2018.09.128
  • Peer Reviewed / Open Access
• [Journal Article] Emergence of immunoregulatory Ym1+Ly6Chi monocytes during recovery phase of tissue injury (2018)
  • Author(s): Ikeda Naoki、Asano Kenichi、Kikuchi Kenta、Uchida Yoshimi、Ikegami Hiroki、Takagi Ryo、Yotsumoto Satoshi、Shibuya Takumi、Makino-Okamura Chieko、Fukuyama Hidehiro、Watanabe Takashi、Ohmuraya Masaki、Araki Kimi、Nishitai Gen、Tanaka Masato
  • Journal Title: Sci Immunol. Volume: 3
  • DOI: 10.1126/sciimmunol.aat0207
  • Peer Reviewed
• [Journal Article] A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations (2018)
  • Author(s): Pastorino,S.,Yoshikawa,Y.,Pass,HI.,Emi,M.,Nasu,M.Pagano,I.Takinishi,Y.,Yamamoto,R.Minaai,M.,Hashimoto_Tamaoki,T.,Ohmuraya,M.,Goto,K.,Goparaju,C.,Sarin,KY.,Tanji,M.,Bononi,A.,Napolitano,A.,Gaudino,G.,Hesdorffer,M.,Yang,H.,Carbone,M.
  • Journal Title: J Clin Oncol. Volume: 印刷中 Pages: 3485-3494
  • DOI: 10.1200/jco.2018.79.0352
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics (2017)
  • Author(s): Akaike Takaaki、、、Nishida Motohiro（4）、、、、、、Fujii Shigemoto（20）、、、Motohashi Hozumi（26）
  • Journal Title: Nature Commun Volume: 8 Pages: 1-10
  • DOI: 10.1038/s41467-017-01311-y
  • NAID: 120007134656
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Significance of lymph node metastasis in pancreatic neuroendocrine tumor. (2017)
  • Author(s): Taki K, Hashimoto D, Nakagawa S, Ozaki N, Tomiyasu S, Ohmuraya M, Arima K, Kaida T, Higashi T, Sakamoto K, Sakata K, Okabe H, Nitta H, Hayashi H, Chikamoto A, Beppu T, Takamori H, Hirota M, Baba H.
  • Journal Title: Surgery Today Volume: 47 Pages: 1104-1110
  • DOI: 10.1007/s00595-017-1485-y
  • Peer Reviewed
• [Journal Article] Surgery for metastatic tumors of the pancreas. (2017)
  • Author(s): Yagi T, Hashimoto D, Taki K, Yamamura K, Chikamoto A, Ohmuraya M, Beppu T, Baba H.
  • Journal Title: Surgical Case Reports Volume: - Pages: 31-31
  • DOI: 10.1186/s40792-017-0308-0
  • Peer Reviewed
• [Journal Article] Depletion of myeloid cells exacerbates hepatitis and induces an aberrant increase in histone H3 in mouse serum (2017)
  • Author(s): Piao X, Yamazaki S, Komazawa-Sakon S, Miyake S, Nakabayashi O, Kurosawa T, Mikami T, Tanaka M, Van Rooijen N, Ohmuraya M, Oikawa A, Kojima Y, Kakuta S, Uchiyama Y, Tanaka M, Nakano H.
  • Journal Title: Hepatology Volume: 65 Pages: 237-252
  • DOI: 10.1002/hep.28878
  • NAID: 120006528815
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Novel method to rescue a lethal phenotype through integration of target gene onto the X-chromosome (2016)
  • Author(s): Sakata K, Araki K, Nakano H, Nishina T, Komazawa-Sakon S, Murai S, Lee GE, Hashimoto D, Suzuki C, Uchiyama Y, Notohara K, Gukovskaya AS, Gukovsky I, Yamamura KI, Baba H, Ohmuraya M.
  • Journal Title: Sci Rep Volume: 6 Pages: 37200-37200
  • DOI: 10.1038/srep37200
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. (2016)
  • Author(s): Yoshikawa Y, Emi M, Hashimoto-Tamaoki T, Ohmuraya M, Sato A, Tsujimura T, Hasegawa S, Nakano T, Nasu M, Pastorino S, Szymiczek A, Bononi A, Tanji M, Pagano I, Gaudino G, Napolitano A, Goparaju C, Pass HI, Yang H, Carbone M.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 113 Pages: 13432-13437
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] C-Type Lectin Receptor DCAR Recognizes Mycobacterial Phosphatidyl-Inositol Mannosides to Promote a Th1 Response during Infection (2016)
  • Author(s): Toyonaga K, Torigoe S, Motomura Y, Kamichi T, Hayashi JM, Morita YS, Noguchi N, Chuma Y, Kiyohara H, Matsuo K, Tanaka H, Nakagawa Y, Sakuma T, Ohmuraya M, Yamamoto T, Umemura M, Matsuzaki G, Yoshikai Y, Yano I, Miyamoto T, Yamasaki S.
  • Journal Title: Immunity. Volume: 45 Pages: 1245-1257
  • DOI: 10.1016/j.immuni.2016.10.012
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1. (2016)
  • Author(s): Ishikawa, E., Kosako, H., Yasuda, T., Ohmuraya, M., Araki, K., Kurosaki, T., Saito, T. and Yamasaki, S.
  • Journal Title: Nat. Commun. Volume: 7 Pages: 12756-12756
  • DOI: 10.1038/ncomms12756
  • NAID: 120006535062
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Cell Death in Pancreatitis (2018)
  • Author(s): Masaki Ohmuraya
  • Organizer: Australia-Japan Meeting on Cell Death
  • Int'l Joint Research
• [Presentation] 膵腺房細胞におけるカテプシン、リソソーム-オートファジー系と膵炎発症の関わり (2018)
  • Author(s): 橋爪慎介、岩間英明、今坂舞、大村谷昌樹
  • Organizer: 第26回 若手膵臓研究会
• [Presentation] ネクローシスが担う生体応答機構の解明 (2018)
  • Author(s): 今坂舞、李未悠、大村谷昌樹
  • Organizer: 第26回 若手膵臓研究会
• [Presentation] デジタルMLPAで高頻度に検出される悪性中皮腫におけるTP53遺伝子の構造異常 (2018)
  • Author(s): 吉川良恵、大村谷昌樹、玉置知子、江見充
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] X染色体不活性化による遺伝子改変慢性膵炎モデルマウスの樹立 (2017)
  • Author(s): 大村谷 昌樹、坂田 和也、橋本 大輔、能登原憲司
  • Organizer: 日本膵臓学会
• [Presentation] 慢性膵炎とカテプシンの役割 (2016)
  • Author(s): 大村谷昌樹
  • Organizer: 第10回オートファジー研究会
  • Place of Presentation: NASPA ニューオータニ、越後湯沢
  • Year and Date: 2016-11-14
• [Presentation] ネクロプトーシスと遺伝性膵炎 (2016)
  • Author(s): 大村谷昌樹
  • Organizer: 第25回 Cell Death学会学術集会
  • Place of Presentation: 品川区立総合区民会館、東京
  • Year and Date: 2016-09-09
• [Presentation] The Roles of Cathepsin B, D, and L during Acute and Chronic Pancreatitis in Mice (2016)
  • Author(s): Masaki Ohmuraya
  • Organizer: 20th meeting of the International Association of Pancreatology
  • Place of Presentation: Sendai International Center, Sendai
  • Year and Date: 2016-04-04
  • Int'l Joint Research / Invited
• [Presentation] 膵、肝臓発生におけるBeclin 1; Becn1の機能解析 (2016)
  • Author(s): 大村谷昌樹、今中応亘
  • Organizer: 第24回 若手膵臓研究会
  • Place of Presentation: 生田神社会館、神戸
• [Book] 新膵臓病学 (2017)
  • Author(s): 下瀬川徹 編集
  • Total Pages: 515
  • Publisher: 南江堂