Mechanisms of liver carcinogenesis through phospho-Smad by gene-targeted mice

• Project/Area Number: 22390153
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kansai Medical University
• Principal Investigator: MATSUZAKI Koichi 関西医科大学, 医学部, 准教授 (70278638)
• Co-Investigator(Kenkyū-buntansha): OKAZAKI Kazuichi 関西医科大学, 医学部, 教授 (70145126) ; SEKI Toshihito 関西医科大学, 医学部, 教授 (70163087)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2011: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2010: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: TGF-β / Smad / Liver fibrosis / Carcinogenesis / TGF-beta / JNK / CDK / シグナル伝達 / 肝発がん / 肝線維化 / 肝発癌

Research Abstract

During progression of chronic liver diseases, chronic inflammation together with somatic mutations shifts hepatocytic phospho-Smad signaling from tumor-suppression to fibro-carcinogenesis, accelerating liver fibrosis and increasing risk of liver cancer. Patients with mild fibrosis respond effectively to therapy by successfully switching Smad phospho-isoform signaling from fibro-carcinogenesis to tumor-suppression, while other therapy responders with advanced liver fibrosis do not (Cytokine & Growth Factor Review in press; Hepatology Research Epub ahead of print).

Research Products

• [Journal Article] Phosphorylated Smad2 and Smad3 signaling: Shifting between tumor suppression and fibro-carcinogenesis in chronic hepatitis C. (2013)
  • Author(s): Yamaguchi T, Matsuzaki K, Inokuchi R, Kawamura R, Yoshida K, Murata M, Fujisawa J, Fukushima N, Sata M, Kage M, Nakashima O, Tamori A, Kawada N, Tsuneyama K, et al.
  • Journal Title: Hepatol Res. Volume: (In press) Issue: 12 Pages: 1327-42
  • DOI: 10.1111/hepr.12082
  • Peer Reviewed
• [Journal Article] TGF-β-activated Kinase 1 (Tak1) Mediates Agonist-induced Smad activation and linker region phosphorylation in embryonic craniofacial neural crest-derived cells. (2013)
  • Author(s): Yumoto K, Thomas S, Matsuzaki K.
  • Journal Title: J Biol Chem Volume: 288 Issue: 19 Pages: 13467-80
  • DOI: 10.1074/jbc.m112.431775
  • Peer Reviewed
• [Journal Article] Phosphorylated Smad2 and Smad3 signaling: Shifting between tumor suppression and fibro-carcinogenesis in chronic hepatitis C (2013)
  • Author(s): Takashi Yamaguchi, Koichi Matsuzaki
  • Journal Title: Hepatology Research Volume: 43
  • Peer Reviewed
• [Journal Article] Tak1 mediates agonist-induced rSmad activation and linker region phosphorylation in the neural crest-derived ectomesenchyme during craniofacial development (2013)
  • Author(s): Kenji Yumoto, Penny S. Thomas, Koichi Matsuzaki
  • Journal Title: Journal of Biological Chemistry Volume: 288
  • Peer Reviewed
• [Journal Article] TGF-β Signaling in Onset and Progression ofHepatocellular Carcinoma. (2012)
  • Author(s): Meindl-Beinker M, Matsuzaki K.
  • Journal Title: Digestive Dis Volume: 30 Issue: 5 Pages: 514-23
  • DOI: 10.1159/000341704
  • Peer Reviewed
• [Journal Article] Differential regulation of TGF-β/Smad signaling in hepatic stallate cells between acute and chronic liver injuries. (2012)
  • Author(s): Yoshida K, Matsuzaki K.
  • Journal Title: Frontiers in Physiology Volume: 53 Pages: 1-7
  • DOI: 10.3389/fphys.2012.00053
  • Peer Reviewed
• [Journal Article] Smadphosphoisoform signals in acute and chronic liver injury: similarities and differences between epithelial and mesenchymal cells (2012)
  • Author(s): Matsuzaki K.
  • Journal Title: Cell & Tissue Res Volume: 347 Issue: 1 Pages: 225-43
  • DOI: 10.1007/s00441-011-1178-6
  • Peer Reviewed
• [Journal Article] Decreased levels of active SMAD2 correlate with poor prognosis in gastric cancer (2012)
  • Author(s): Yijun Wu, Qi Li, Jiren Yu, Yunchuan Mu, Stefan Munker, Chengfu Xu, Zhe Shen, Roman Müllenbach, Yan Liu, Li Li, Norbert Gretz, Derek Zieker, Jun Li, Koichi Matsuzaki
  • Journal Title: PLoS ONE Volume: 7
  • Peer Reviewed
• [Journal Article] Smad phosphoisoform signals in acute and chronic liver injury: similarities and differences between epithelial and mesenchymal cells (2012)
  • Author(s): Koichi Matsuzaki
  • Journal Title: Cell & Tissue Res Volume: 347 Pages: 225-243
  • Peer Reviewed
• [Journal Article] Modulation of TGF-β/Smad signaling in hepatic stellate cells during chronic liver injury (2012)
  • Author(s): Katsunori Yoshida K and Koichi Matsuzaki
  • Journal Title: Frontiers in Gastrointestinal Science Volume: 3 Pages: 1-7
  • Peer Reviewed
• [Journal Article] TGF-β Signaling in Onset and Progression of Hepatocellular Carcinoma (2012)
  • Author(s): Meindl-Beinker N.M., Matsuzaki K., and Dooley S
  • Journal Title: Digestive Diseases Volume: 30 Pages: 514-523
  • Peer Reviewed
• [Journal Article] The specific linker phosphorylation of Smad2/3 indicates epithelial stem cells in stomach ; particularly increasing in mucosae of Helicobacter-associated gastritis (2011)
  • Author(s): Toshiro Fukui
  • Journal Title: Journal of Gastroenterology Volume: 46 Issue: 4 Pages: 456-168
  • DOI: 10.1007/s00535-010-0364-8
  • Peer Reviewed
• [Journal Article] Oncogenic Smad3 signaling induced by chronic inflammation is an early event in ulcerative colitis-associated carcinogenesis. (2011)
  • Author(s): Kawamata S, Matsuzaki K, et al.
  • Journal Title: Inflammatory Bowel Dis Volume: 7 Issue: 3 Pages: 683-95
  • DOI: 10.1002/ibd.21395
  • Peer Reviewed
• [Journal Article] Smad phosphoisoform signaling specificity: the right place at the righttime. (2011)
  • Author(s): Matsuzaki K.
  • Journal Title: Carcinogenesis Volume: 32 Issue: 11 Pages: 1578-88
  • DOI: 10.1093/carcin/bgr172
  • Peer Reviewed
• [Journal Article] ウイルス性慢性肝疾患におけるリン酸化Smadを介する線維化・がん化シグナル (2011)
  • Author(s): 松崎恒一
  • Journal Title: 日本消化器病学会雑誌 Volume: 108 Pages: 1363-1373
  • NAID: 10030297930
  • Peer Reviewed
• [Journal Article] Smad phosphoisoform signals in acute and chronic liver injury: similarities and differences between epithelial and mesenchymal cells (2011)
  • Author(s): Matsuzaki Koichi
  • Journal Title: Cell & Tissue Research Volume: in press
  • Peer Reviewed
• [Journal Article] The specific linker phosphorylation of Smad2/3 indicates epithelial stem cells in stomach ; particularly increasing in mucosae of Helicobacter-associated gastritis. (2011)
  • Author(s): Fukui T., Kishimoto M., Nakajima A., Yamashina M., Nakayama S., Kusuda T., Sakaguchi Y., Yoshida K., Uchida K., Nishio A., Matsuzaki K., Okazaki K.
  • Journal Title: Journal of Gastroenterology Volume: 46 Pages: 456-468
  • NAID: 10029028438
  • Peer Reviewed
• [Journal Article] Expression of pituitary tumor transforming gene 1 (PTTG1)/securin in hepatitis B virus-associated liver diseases: evidence for a hepatitis B virus X protein-mediated inhibition of PTTG1 ubiquitination and degradation. (2010)
  • Author(s): Molina-Jimenez F, Benedicto I, Seki T,Okazaki K, Matsuzaki K, et al.
  • Journal Title: Hepatology Volume: 51 Issue: 3 Pages: 777-87
  • DOI: 10.1002/hep.23468
  • Peer Reviewed
• [Journal Article] Expression of Pituitary Tumor Transforming Gene I (PTTG1)/Securin in hepatitis B virus-associated liver diseases : Evidence for a Hepatitis B virus X protein-mediated inhibition of PTTG1 ubiquitination and degradation. (2010)
  • Author(s): Molina-Jimenez F, Matsuzaki K, et al.
  • Journal Title: Hepatology Volume: 51 Pages: 777-787
  • Peer Reviewed
• [Journal Article] Smad phospho-isoforms direct context dependentTGF-β signaling
  • Author(s): Matsuzaki K.
  • Journal Title: Cytokine & Growth Factor Review Volume: (in press)
  • Peer Reviewed
• [Journal Article] Decreased levels of active SMAD2 correlate with poor prognosis in gastric cancer
  • Author(s): Yijun Wu, Qi Li, Jiren Yu, Yunchuan Mu, Stefan Munker, Chengfu Xu, Zhe Shen, Roman Mullenbach, Yan Liu, Li Li, Norbert Gretz, Derek Zieker, Jun Li, Koichi Matsuzaki, et al
  • Journal Title: PLoS ONE Volume: (in press)
  • Peer Reviewed
• [Presentation] Reversible phospho-Smad signaling between tumor-suppression andfibro-carcinogenesis in human chronic liver diseases (2013)
  • Author(s): Matsuzaki K.
  • Organizer: The 2nd JSGE International Topic Conference / The 8th JSGE-AGA Joint Meeting
  • Place of Presentation: Kagoshima, Japan
  • Year and Date: 2013-05-02
• [Presentation] 慢性炎症が惹起する前がん病変のがん化シグナルは、治療介入により、がん抑制シグナルに回帰する:TGF-βシグナル伝達からみた臨床検討 (2012)
  • Author(s): 松崎恒一
  • Organizer: 第192回日本消化器病学会東北支部例会
  • Place of Presentation: 仙台国際センター、仙台
  • Year and Date: 2012-02-04
• [Presentation] Smad phosphoisoform signalingspecificity: the right place at the right time (2011)
  • Author(s): Matsuzaki K.
  • Organizer: 70th Annual Meeting of the Japanese CancerAssociation
  • Place of Presentation: Nagoya, Japan.
  • Year and Date: 2011-10-07
• [Presentation] Smad phosphoisoform signaling specificity : the right place at the right time (2011)
  • Author(s): Matsuzaki K.
  • Organizer: 70th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Nagoya congress center, Nagoya, Japan
  • Year and Date: 2011-10-04
• [Presentation] 核酸アナログ治療後、B型慢性肝疾患の線維化・癌化シグナルは、癌抑制シグナルに回帰する (2011)
  • Author(s): 吉田勝紀、Long Qing、松崎恒一
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: ホテルグランパシフィック、東京
  • Year and Date: 2011-06-02
• [Presentation] 原発性胆汁性肝硬変症におけるTGF-βシグナル伝達機構の解析 (2011)
  • Author(s): 川村梨那子、松崎恒一
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: ホテルグランパシフィック、東京
  • Year and Date: 2011-06-02
• [Presentation] Reversible phosphorylatedSmad3 signaling between tumor-suppression and fibro-carcinogenesis in chronic hepatitis C (2011)
  • Author(s): Matsuzaki K.
  • Organizer: The3^<rd> JCA-AACR Special Joint Conference
  • Place of Presentation: Chiba,Japan
  • Year and Date: 2011-05-16
• [Presentation] Reversible phosphorylated Smad3 signaling between tumor-suppression and fibro-carcinoeenesis in chronic hepatitis C (2011)
  • Author(s): Matsuzaki Koichi
  • Organizer: The 3^<rd> JCA AACR Special Joint Conference
  • Place of Presentation: Chiba, Japan
  • Year and Date: 2011-03-02
• [Presentation] Smad3 phosphoisoform-mediated signaling during colorectal cancer using chronic colitis mice model (2010)
  • Author(s): Matsuzaki K., Seki T., Okazaki K.
  • Organizer: 61st Annual Meeting, American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, USA
  • Year and Date: 2010-10-30
• [Presentation] Reversible Smad signaling in chronic liver diseases (2010)
  • Author(s): Matsuzaki Koichi
  • Organizer: Roche round table seminar
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2010-04-17
• [Presentation] Smad signaling in human liver diseases (2010)
  • Author(s): Matsuzaki Koichi
  • Organizer: GastroForschung-Kolloquium-2010
  • Place of Presentation: Heidelberg, Germany
  • Year and Date: 2010-04-15
• [Presentation] Reversible Smad signaling in chronic liver diseases (2010)
  • Author(s): Matsuzaki K.
  • Organizer: Roche round tableseminar, Vienna
  • Place of Presentation: Austria
  • Year and Date: 2010-04-07
• [Presentation] Smad signaling in human liver diseases (2010)
  • Author(s): Matsuzaki K.
  • Organizer: GastroForschung- Kolloquium-2010Heidelberg
  • Place of Presentation: University, Heidelberg, Germany
  • Year and Date: 2010-04-05
• [Presentation] Reversible or irreversible phospho-Smad2/3 signaling between tumor-suppression and fibro-carcinogenesis in hepatitis C virus-related chronic liver diseases
  • Author(s): Miki Murata, Koichi Matsuzaki
  • Organizer: The 2nd International Symposium by JSPS Core-to-Core Program "Cooperative International Framework in TGF-β Family Signaling" TGF-β Family: Signal Network and Tumor Microenvironment
  • Place of Presentation: 昭和薬科大学（東京）
• [Presentation] Reversible phospho-Smad3 signaling between tumor-suppression and fibro-carcinogenesis in chronic hepatitis B
  • Author(s): Katsunori Yoshida, Koichi Matsuzaki
  • Organizer: The 2nd International Symposium by JSPS Core-to-Core Program "Cooperative International Framework in TGF-β Family Signaling" TGF-β Family: Signal Network and Tumor Microenvironment
  • Place of Presentation: 昭和薬科大学（東京）
• [Presentation] Reversible or irreversible phospho-Smad3 signaling between tumor-suppression and fibro-carcinogenesis in hepatitis C virus-related chronic liver diseases
  • Author(s): Katsunori Yoshida, Koichi Matsuzaki
  • Organizer: The 10th JSH Single topic conference "Hepatitis C: Best practice based on science", Tokyo, Japan
  • Place of Presentation: 京王プラザホテル（東京）
• [Presentation] Reversible phospho-Smad signaling between tumor-suppression and fibro-carcinogenesis in human chronic liver diseases
  • Author(s): Koichi Matsuzaki
  • Organizer: The 2nd JSGE International Topic Conference / The 8th JSGE-AGA Joint Meeting
  • Place of Presentation: 城山観光ホテル（鹿児島）
  • Invited
• [Presentation] 急性肝障害時の肝細胞ならびに肝星細胞におけるTGF-βシグナル伝達の検討
  • Author(s): 村田美樹、松崎恒一
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 全日空ホテル（金沢）
• [Book] Future Outlook. In Hepatocellular Carcinoma (2013)
  • Author(s): Murata M., Yoshida K., and Matsuzaki K
  • Total Pages: 10
  • Publisher: InTech &#8211; open science
• [Book] Future Outlook. In Hepatocellular Carcinoma (ed. Daria Nahtigel). Early chronic inflammation and subsequent somatic mutations shift phospho-Smad3 signaling from tumor-suppression to fibro-carcinogenesis in human chronic liver diseases.
  • Author(s): Murata M, Yoshida K, and Matsuzaki K
  • Publisher: InTech - open science
• [Patent(Industrial Property Rights)] リンカー領域がリン酸化された Smad3を特異的に認識するモノクローナル抗体 (2012)
  • Inventor(s): 瀬川辰也、清藤勉、松崎恒一
  • Industrial Property Rights Holder: 株式会社免疫生物研究所
  • Filing Date: 2012-07-07
• [Patent(Industrial Property Rights)] リンカー領域がリン酸化されたSmad3を特異的に認識するモノクローナル抗体 (2012)
  • Inventor(s): 瀬川辰也、清藤勉、松崎恒一
  • Industrial Property Rights Holder: 瀬川辰也、清藤勉、松崎恒一
  • Industrial Property Rights Type: 特許
  • Filing Date: 2012