Molecular analysis of novel tumor suppressor RUNX3 in gastric cancers and its clinical application

• Project/Area Number: 19390354
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: SAKAKURA Chouhei Kyoto Prefectural University of Medicine, 医学研究科, 講師 (10285257)
• Co-Investigator(Kenkyū-buntansha): OKUDA Tsukasa 京都府立医科大学, 医学研究科, 准教授 (30291587) ; CHIBA Tsutomu 京都大学, 大学院・医学研究科, 教授 (30188487) ; 萩原 明郎 京都府立医科大学, 医学研究科, 准教授 (90198648)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000); Fiscal Year 2008: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2007: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: RUNX3 / 胃癌 / 遺伝子診断 / 胃十二指腸外科 / 癌抑制遺伝子

Research Abstract

我々は、世界に先駆けてRunx3ノックアウトマウスを作製し、その解析よりRUNX3遺伝子が胃粘膜の発生や分化に重要な役割をはたしており、この異常が胃粘膜の脱分化や異常増殖や癌化に関連することを示した。さらに将来的にはこれらに基づく胃粘膜の発癌リスク予測や胃癌の転移予測などの遺伝子診断や遺伝子治療を目指しており、胃癌の発癌予防や消化管粘膜再生にも応用しうると考えている。またRUNX3遺伝子の関与する疾患は主に胃癌と考えられていたが、我々は、肝細胞癌、膵臓癌、大腸癌においてもRUNX3遺伝子の関与の可能性を示唆するデータを得ており(Oncogene, 2004, 2007)、これらの癌においてもRUNX3遺伝子の異常を指標とした遺伝子診断や遺伝子治療への応用を行ないつつある。
RUNX3はTGFβ依存性アポプトーシスに重要な役割を果たしており、食道扁平上皮癌における放射線化学療法の感受性に関与していることが明らかになった(Oncogene, 2007)。またRUNX3遺伝子の関与する疾患は主に胃癌と考えられていたが、RUNX3メチル化を指標とした定量メチル化診断システムを用いた血清診断は従来の腫瘍マーカーを補完しうる新しい胃癌の血清診断マーカーになりうる可能性が示唆された (Anticancer Res. 2009, in press)。さらに我々は日立ソフトLuminexシステムにより、多数の検体における複数遺伝子のメチル化を定量的に短時間で測定しうる迅速血清診断システムを確立し、実地臨床に応用しつつある。

Research Products

• [Journal Article] Attenuated response to liver injury in moesin-deficient mice : Impaired stellate cell migration and decreased fibrosis (2008)
  • Author(s): Okayama T, Kikuchi S, Ochiai T, Ikoma H, Kubota T, Ichikawa D, Fujiwara H, Okamoto K, Sakakura C , Sonoyama T, Kokuba Y, Doi Y, Tsukita S, Bissell DM, Otsuji E
  • Journal Title: Biochim Biophys Acta. 1782(9) Pages: 542-8
  • Peer Reviewed
• [Journal Article] Overexpression of RegIV in peritoneal dissemination of gastric cancer and its potential as a novel marker for the detection of peritoneal micrometastasis (2008)
  • Author(s): Miyagawa K, Sakakura C, Nakashima S, Yoshikawa T, Fukuda K, Kin S, Nakase Y, Shimomura K, Oue N, Yasui W, Hayasizaki H, Okazaki Y, Yamagishi H, Hagiwara A, Otsuji E
  • Journal Title: (These authors are equally contributed)Anticancer Res. 28(2B) Pages: 1169-79
  • Peer Reviewed
• [Journal Article] Repression of the transcription factor Th-POK by Runx complexes in cytotoxic T cell development (2008)
  • Author(s): Setoguchi R, Tachibana M, Naoe Y, Muroi S, Akiyama K, Tezuka C, Okuda T, Taniuchi I
  • Journal Title: Science 319(5864) Pages: 822-5
  • Peer Reviewed
• [Journal Article] AML1/runx1 works as a negative regulator of C-MPL in hematopoietic stem cells (2008)
  • Author(s): Satoh Y, Matsumura I, Tanaka H, Ezoe S, Fukushima K, Tokunaga M, Yasumi M, Shibayama H, Mizuki M, Era T, Okuda T, Kanakura Y
  • Journal Title: J Biol Chem. 283(44) Pages: 30045-56
  • Peer Reviewed
• [Journal Article] Activation-induced cytidine deaminase links between inflammation and the development of colitis-associated colorectal cancers (2008)
  • Author(s): Endo Y, Marusawa H, Kou T, Nakase H, Fujii S, Fujimori T, Kinoshita K, Honjo T, Chiba T
  • Journal Title: Gastroenterology 135(3) Pages: 889-98
  • Peer Reviewed
• [Journal Article] Parkin as tumor suppressor gene for hepatocellular carcinoma (2008)
  • Author(s): Fujiwara M, Marusawa H, Wang HQ, Iwai A, Ikeuchi K, Imai Y, Kataoka A, Nukina N, Takahashi R, Chiba T
  • Journal Title: Oncogene 27(46) Pages: 6002-11
  • Peer Reviewed
• [Journal Article] Fatal Autoimmune Hepatitis Induced by Concurrent Loss of Naturally Arising Regulatory T Cells and PD-1-Mediated Signaling (2008)
  • Author(s): Kido M, Watanabe N, Okazaki T, Akamatsu T, Tanaka J, Saga K, Nishio A, Honjo T, Chiba T
  • Journal Title: Gastroenterology 135(4) Pages: 1333-43
  • Peer Reviewed
• [Journal Article] Limited benefit of biochemical response to combination therapy for patients with recurrent hepatitis C after living-donor liver transplantation (2008)
  • Author(s): Ueda Y, Takada Y, Haga H, Nabeshima M, Marusawa H, Ito T, Egawa H, Tanaka K, Uemoto S, Chiba T
  • Journal Title: Transplantation. 85(6) Pages: 855-62
  • Peer Reviewed
• [Journal Article] Biliary complications in donors for living donor liver transplantation (2008)
  • Author(s): Shio S, Yazumi S, Ogawa K, Hasegawa K, Tsuji Y, Kida M, Yamauchi J, Ida H, Tada S, Uemoto S, Chiba T
  • Journal Title: Am J Gastroenterol. 103(6) Pages: 1393-8
  • Peer Reviewed
• [Journal Article] Attenuated response to liver injury in moesin-deficient mice : Impaired stellate cell migration and decreased fibrosis. (2008)
  • Author(s): Okayama T, Kikuchi S, Ochiai T, Ikoma H, Kubota T, Ichikawa D, Fuiiwara H, Okamoto K, Sakakura C, Sonoyama T, Kokuba Y, Doi Y, Tsukita S, Bissell DM, Otsuji E.
  • Journal Title: Biochim Biophys Acta. 1782(9) Pages: 542-548
  • Peer Reviewed
• [Journal Article] Overexpression of RegIV in peritoneal dissemination of gastric cancer and its potential as a novel marker for the detection of peritoneal micrometastasis. (2008)
  • Author(s): Miyagawa K^*, Sakakura C*, Nakashima S, Yoshikawa T, Fukuda K, Kin S, Nakase Y, Shimomura K, Oue N, Yasui W, Hayasizaki H, Okazaki Y, Yamagishi H, Hagiwara A, Otsuii E. (^*These authors areequallv contributed)
  • Journal Title: Anticancer Res. 28(2B) Pages: 1169-79
  • Peer Reviewed
• [Journal Article] Intrathoracic esophageal replacement by in situ tissue-engineered esophagus. (2008)
  • Author(s): Nakase Y, Nakamura T, Kin S, Nakashima S, Yoshikawa T, Kuriu Y, Sakakura C, Yamagishi H, Hamuro J, Ikada Y, Otsuji E, Hagiwara A.
  • Journal Title: J Thorac Cardiovasc Surg. 136(4) Pages: 850-9
  • Peer Reviewed
• [Journal Article] 新しい胃癌の癌抑制遺伝子RUNX3の解析からH. pyloriと胃発癌の関連を探る (2008)
  • Author(s): 阪倉長平, 西尾 実, 小西英幸, 大辻英吾
  • Journal Title: Helicobacter Research 12(4) Pages: 252-8
• [Journal Article] Serum concentration of Reg IV in patients with colorectal cancer : overexpression and high serum levels of Reg IV are associated with liver metastasis (2007)
  • Author(s): Oue N, Kuniyasu H, Noguchi T, Sentani K, Ito M, Tanaka S, Setoyama T, Sakakura C, Natsugoe S, Yasui W
  • Journal Title: Oncology(Epub 2008) 72(5-6) Pages: 371-80
  • Peer Reviewed
• [Journal Article] Regeneration of skeletal muscle using in situ tissue engineering on an acellular collagen sponge scaffold in a rabbit model (2007)
  • Author(s): Kin S, Hagiwara A, Nakase Y, Kuriu Y, Nakashima S, Yoshikawa T, Sakakura C, Otsuji E, Nakamura T, Yamagishi H
  • Journal Title: ASAIO J. 53(4) Pages: 506-13
  • Peer Reviewed
• [Journal Article] Restoration of RUNX3 enhances transforming growth factor-beta-dependent p21 expression in a biliary tract cancer cell line (2007)
  • Author(s): Hasegawa K, Yazumi S, Wada M, Sakurai T, Kida M, Yamauchi J, Hisatsune H, Tada S, Ida H, Nakase Y, Sakakura C, Hagiwara A, Chiba T
  • Journal Title: Cancer Sci. 98(6) Pages: 838-43
  • Peer Reviewed
• [Journal Article] Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis (2007)
  • Author(s): Sakakura C, Miyagawa K, Fukuda KI, Nakashima S, Yoshikawa T, Kin S, Nakase Y, Ida H, Yazumi S, Yamagishi H, Okanoue T, Chiba T, Ito K, Hagiwara A, Ito Y
  • Journal Title: Oncogene 26(40) Pages: 5927-38
  • Peer Reviewed
• [Journal Article] Endocrine cell and nerve regeneration in autologous in situ tissue-engineered small intestine (2007)
  • Author(s): Nakase Y, Nakamura T, Kin S, Nakashima S, Yoshikawa T, Kurou Y, Miyagawa K, Sakakura C, Otsuji E, Ikada Y, Yamagishi H, Hagiwara A
  • Journal Title: J Surg Res 137(1) Pages: 61-68
  • Peer Reviewed
• [Journal Article] In situ Tissue Engineering of the Bile Duct Using Polypropylene Mesh-Collagen Tubes (2007)
  • Author(s): Nakashima S, Nakamura T, Miyagawa K, Yoshikawa T, Kin S, Kuriu Y, Nakase Y, Sakakura C, Otsuji E, Hagiwara A and Yamagishi H
  • Journal Title: Int J of Art Org 30(1) Pages: 75-85
  • Peer Reviewed
• [Journal Article] Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium (2007)
  • Author(s): Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa T, Azuma T, Okazaki IM, Honjo T, Chiba T
  • Journal Title: Nat Med. 13(4) Pages: 470-6
  • Peer Reviewed
• [Journal Article] Regeneration of skeletal muscle using in situ tissue engineering on an acellular collagen sponge scaffold in arabbit model. (2007)
  • Author(s): Kin S, Hagiwara A, Nakase Y, Kuriu Y, Nakashima S, Yoshikawa T, Sakakura C, et. al.
  • Journal Title: ASAIO J. 53(4) Pages: 506-13
  • Peer Reviewed
• [Journal Article] Restoration of RUNX3 enhances transforming growth factor-beta-dependent p21 expression in a biliary tract cancer cell line. (2007)
  • Author(s): Hasegawa K, Yazumi S, Wada M, Sakurai T, Kida M, Yamauchi J, Hisatsune H, Tada S, Ida H, Nakase Y, Sakakura C, et. al.
  • Journal Title: Cancer Sci. 98(6) Pages: 838-43
  • Peer Reviewed
• [Journal Article] Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis. (2007)
  • Author(s): Sakakura C, et. al.
  • Journal Title: Oncogene. 26(40) Pages: 5927-38
  • Peer Reviewed
• [Journal Article] Endocrine cell and nerve regeneration in autologous in situtissue-engineered small intestine (2007)
  • Author(s): Nakase Y, Nakamura T, Kin S, Nakashima S, Yoshikawa T, Kurou Y, Miyagawa K, Sakakura C, et. al.
  • Journal Title: J Surg Res 137(1) Pages: 61-68
  • Peer Reviewed
• [Journal Article] Quantitative Analysis of Tumor-derived Methylated RUNX3 Sequences in the Serum of Gastric Cancer Patients
  • Author(s): Sakakura C, Hamada T, Nishio M, Miyagawa K, Miyashita A, Nagata H, Kin S, Fukuda K, Nakase Y, Hagiwara A, Nakanishi M, Yamazaki J Yoshikawa S, Okamoto K, Kokuba Y, and Otsuji E
  • Journal Title: Anticancer Res (in press)
• [Journal Article] Laparoscope-assisted superlow anterior resection combined with inter-sphincteric rectal dissection for very low advanced rectal cancers combined with preoperative chemotherapy
  • Author(s): Sakakura C, Nishio M, MiyagawaK,Miyashita A, Nagata H, Kin S, Fukuda K, Nakase Y, Hagiwara A, Nakanishi M, Yamazaki J, Yoshikawa S, Okamoto K, Kokuba Y, and Otsuji E
  • Journal Title: Hepatogastroenterology (in press)
• [Presentation] 新しい胃癌の癌抑制遺伝子RUNX3の細胞分化・癌化機構の解析とトランスレーショナルリサーチへの応用 (2008)
  • Author(s): 阪倉長平、大辻英吾、伊藤嘉明
  • Organizer: 第50回日本消化器病学会
  • Place of Presentation: 東京
  • Year and Date: 2008-10-03
• [Presentation] 新しい胃癌の癌抑制遺伝子RUNX3の細胞分化・癌化機構の解析とトランスレーショナルリサーチヘの応用ワークショップ (2008)
  • Author(s): 阪倉長平, 大辻英吾, 伊藤嘉明
  • Organizer: 第50回日本消化器病学会
  • Place of Presentation: 東京
  • Year and Date: 2008-10-03
• [Presentation] 新しい胃癌の癌抑制遺伝子RUNX3の細胞分化・癌化機構の解析とトランスレーショナルリサーチへの応用 (2008)
  • Author(s): 阪倉長平、西尾実、宮下篤史、生駒久視、中西正芳、窪田健、市川大輔、菊池正二郎、藤原 斉、岡本和真、落合登志哉、国場幸均、谷口弘毅、園山輝久、千葉勉、大辻英吾、伊藤嘉明
  • Organizer: 第63回日本消化器外科学会
  • Place of Presentation: 札幌
  • Year and Date: 2008-07-21
• [Presentation] 新しい胃癌の癌抑制遺伝子RUNX3の細胞分化・癌化機構の解析とトランスレーショナルリサーチヘの応用ワークショップ (2008)
  • Author(s): 阪倉長平, 西尾 実, 宮下 篤史, 生駒久視, 中西正芳, 窪田健, 市川大輔, 菊池正二郎, 藤原 斉, 岡本和真, 落合登志哉, 国場幸均, 谷口弘毅, 園山輝久, 千葉 勉, 大辻英吾, 伊藤嘉明
  • Organizer: 第63回日本消化器外科学会
  • Place of Presentation: 札幌
  • Year and Date: 2008-07-21
• [Presentation] 新しい胃癌の癌抑制遺伝子RUNX3の細胞分 化・癌化機構の解析とトランスレーショナ ルリサーチへの応用 (2008)
  • Author(s): 阪倉長平、大辻英吾、伊藤嘉明
  • Organizer: 第17回日本癌治療病態研究会
  • Place of Presentation: 京都
  • Year and Date: 2008-05-21
• [Presentation] 新しい胃癌の癌抑制遺伝子RUNX3の細胞分化・癌化機構の解析とトランスレーショナルリサーチヘの応用ワークショップ (2008)
  • Author(s): 阪倉長平, 大辻英吾, 伊藤嘉明
  • Organizer: 第17回日本癌治療病態研究会
  • Place of Presentation: 京都
  • Year and Date: 2008-05-21
• [Presentation] 新しい胃癌の癌抑制遺伝子RUNX3の細胞分化・癌化機構の解明と予防・診断への応用 (2007)
  • Author(s): 阪倉長平、宮川公治、金修一、中瀬有遠、福田賢一郎、中島 晋、吉川徹二、萩原明於、山岸久一、伊藤公成、伊藤嘉明
  • Organizer: 第61回日本消化器外科学会
  • Place of Presentation: 東京
  • Year and Date: 2007-07-21
• [Presentation] 新しい胃癌の癌抑制遺伝子RUNX3の細胞分化・癌化機構の解明と予防・診断への応用 (2007)
  • Author(s): 阪倉長平
  • Organizer: 第61回日本消化器外科学会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2007-07-21
• [Presentation] 新しい胃癌の癌抑制遺伝子RUNX3の細胞分化・癌化機構の解明と診断・治療への応用 (2007)
  • Author(s): 阪倉長平、宮川公治、金修一、中瀬有遠、福田賢一郎、中島 晋、吉川徹二、萩原明於、山岸久一、伊藤公成、伊藤嘉明
  • Organizer: 第79回日本胃癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-02-25