がん細胞の分化異常とチロシンキナーゼ制御

• 研究課題/領域番号: 17014069
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 慶應義塾大学 (2008-2009); 九州大学 (2005-2007)
• 研究代表者: 吉村 昭彦 慶應義塾大学, 医学部, 教授 (90182815)
• 研究期間 (年度): 2005 – 2009
• 研究課題ステータス: 完了 (2009年度)
• 配分額: 59,900千円 (直接経費: 59,900千円); 2009年度: 12,900千円 (直接経費: 12,900千円); 2008年度: 12,900千円 (直接経費: 12,900千円); 2007年度: 11,400千円 (直接経費: 11,400千円); 2006年度: 11,400千円 (直接経費: 11,400千円); 2005年度: 11,300千円 (直接経費: 11,300千円)
• キーワード: サイトカイン / シグナル伝達 / チロシンキナーゼ / 転写因子 / STAT / 炎症 / Ras / ERK / 家族性変異 / 発がん / Spred / 神経繊維腫I型 / SOCS / Sred / 肝炎 / 肝がん / チロシンりん酸化 / インターフェロン

研究概要

がん組織内に浸潤する炎症細胞はさまざまなメディエーターを介してがんの増殖や増悪化に寄与する。このなかで炎症性サイトカインはがん細胞においてNF-・BやJAK-STAT経路を活性化する。我々はサイトカインの抑制因子であるSOCSとSpredについて癌との関連について研究を行った。モデルマウスではSOCS1やSOCS3の欠損によってがん化が促進され、またヒト肝臓がんにおいてSOCS遺伝子のサイレンシングが寄与することが明らかとなってきた。さらに我々は癌と関連の深いRas/ERK経路の抑制因子であるSpred1の変異を神経繊維腫I型に見いだした。

研究成果

• [雑誌論文] Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. (2009)
  • 著者名/発表者名: Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, Iwakura Y, Yoshimura A
  • 雑誌名: Nature Med. 15(8) ページ: 946-950
• [雑誌論文] SOCS3 in T and NKT cells negatively regulates cytokine production and ameliorates ConA-induced hepatitis. (2009)
  • 著者名/発表者名: Nakaya M, Hashimoto M, Nakagawa R, Wakabayashi Y, Ishizaki T, Takada I, Komai K, Yoshida H, Yoshimura A
  • 雑誌名: J Immunol 183(11) ページ: 7047-7053
• [雑誌論文] Clinical and mutational spectrum of Legius syndrome (2009)
  • 著者名/発表者名: Messiaen L, Yao S, (他30名), Taniguchi K, Ayada T, Okamoto F, Yoshimura A, Parret A, Korf B, Legius E
  • 雑誌名: JAMA 302(19) ページ: 2111-2118
• [雑誌論文] Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. (2009)
  • 著者名/発表者名: Taleb S, Romain M, Ramkhelawon B, Uyttenhove C, Pasterkamp G, Herbin O, Esposito B, Perez N, Yasukawa H, Van Snick J, Yoshimura A, Tedgui A, Mallat Z
  • 雑誌名: J Exp Med. 206(10) ページ: 2067-2077
• [雑誌論文] Suppression of Sproutys has a therapeutic effect for a mouse model of ischemia by enhancing angiogenesis. (2009)
  • 著者名/発表者名: Taniguchi K, Sasaki K, Watari K, Yasukawa H, Imaizumi T, Ayada T, Okamoto F, Ishizaki T, Kato R, Kohno R, Kimura H, Sato Y, Ono M, Yonemitsu Y, Yoshimura A
  • 雑誌名: PLoS ONE 4(5)
• [雑誌論文] Cyclic adenosine monophosphate suppresses the transcription of proinflammatory cytokines via the c-Fos protein phosphorylated by IKKbeta (2009)
  • 著者名/発表者名: Koga K, Takaesu G, Yoshida R, Nakaya M, Kobayashi T, Kinjyo I, Yoshimura A
  • 雑誌名: Immunity 30(3) ページ: 372-383
• [雑誌論文] Silencing of SOCS1 in macrophages suppresses tumor development by enhancing antitumor inflammation (2009)
  • 著者名/発表者名: Hashimoto M, Ayada T, Kinjyo I, Hiwatashi K, Yoshida H, Okada Y Kobayashi T, Yoshimura A
  • 雑誌名: Cancer Sci 100(4) ページ: 730-736
  • NAID: 10025144745
• [雑誌論文] Rudensky AY. Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. (2009)
  • 著者名/発表者名: Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K, Loeb GB, Lee H, Yoshimura A, Rajewsky K
  • 雑誌名: Immunity 30(1) ページ: 80-91
• [雑誌論文] Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4, 5-biphosphate hydrolysis. (2009)
  • 著者名/発表者名: Ayada T, Taniguchi K, Okamoto F, Kato R, Komune S, Takaesu G, Yoshimura A
  • 雑誌名: Oncogene 28(8) ページ: 1076-88
• [雑誌論文] Cyclic Adenosine Monophosphate Suppresses the Transcription of Proinflammatory Cytokines via the Phosphorylated c-Fos Protein (2009)
  • 著者名/発表者名: Keiko Koga, et al.
  • 雑誌名: Immunity 30 ページ: 372-383
  • 査読あり
• [雑誌論文] Signal-Transducing Adaptor Protein-2 Regulates Stromal Cell-Derived Factor-1{alpha}-Induced Chemotaxis in T Cells. (2009)
  • 著者名/発表者名: Sekine Y, Ikeda O, Tsuji S, et al.
  • 雑誌名: J Immunol. 183(12) ページ: 7966-7974
  • 査読あり
• [雑誌論文] Clinical and mutational spectrum of Legius syndrome (2009)
  • 著者名/発表者名: Messiaen L, Yao S, Brems H, et al.
  • 雑誌名: JAMA 206(10) ページ: 2067-2077
  • 査読あり
• [雑誌論文] Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. (2009)
  • 著者名/発表者名: Shichita T, Sugiyama Y, Ooboshi H., et al.
  • 雑誌名: Nature Med. 15(8) ページ: 946-950
  • 査読あり
• [雑誌論文] Sprouty4 negatively regulates protein kinase C activation by inhibiting phoshatidylinositol 4,5-biphosphate hydrolysis. (2009)
  • 著者名/発表者名: Ayata T, Taniguchi K, et al.
  • 雑誌名: Oncogene 28 ページ: 1076-1088
  • 査読あり
• [雑誌論文] Sprouty4 deficiency potentiates Ras-independent angiogenic signals and tumor growth. (2009)
  • 著者名/発表者名: Taniguchi K, Ishizaki T, Ayada T, et al.
  • 雑誌名: Cancer Sci. 100(9) ページ: 1648-1654
  • 査読あり
• [雑誌論文] Cyclic Adenosine Monophosphate Suppresses the Transcription of Prninflammatnry Cvtokines via the Phosnhorvlated c-Fos Protein (2009)
  • 著者名/発表者名: Keiko Koga, et.al.
  • 雑誌名: Immunity 30 ページ: 372-383
  • 査読あり
• [雑誌論文] Sprouty4 negatively regulates protein kinase C activation by inhibiting phosnhatidvlinositol 4.5-biphosphate hydrolysis (2009)
  • 著者名/発表者名: Ayata T, Taniguchi K, et.al.
  • 雑誌名: Oncogene 28 ページ: 1076-1088
  • 査読あり
• [雑誌論文] STAT6 inhibits TGF-beta 1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. (2008)
  • 著者名/発表者名: Takaki H, Ichiyama K, Koga K, Chinen T, Takaesu G, Sugiyama Y, Kato S, Yoshimura A, Kobayashi T
  • 雑誌名: J Biol Chem. 283(22) ページ: 14955-14962
• [雑誌論文] TRAF6 and MEKK1 Play a Pivotal Role in the RIG-I-like Helicase Antiviral Pathway. (2008)
  • 著者名/発表者名: Yoshida R, Takaesu G, Yoshida H, Okamoto F, Yoshioka T, Choi Y, Akira S, Kawai T, Yoshimura A, Kobayashi T
  • 雑誌名: J Biol Chem. 283(52) ページ: 36211-36220
• [雑誌論文] FLN29 deficiency reveals its negative regulatory role in the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like helicases signaling pathway. (2008)
  • 著者名/発表者名: Sanada T, Takaesu G, Mashima R, Yoshida R, Kobayashi T, Yoshimura A
  • 雑誌名: J Biol Chem. 283(49) ページ: 33858-33864
• [雑誌論文] Suppressor of cytokine signaling 1 protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis. (2008)
  • 著者名/発表者名: Torisu T, Nakaya M, Watanabe S, Hashimoto M, Yoshida H, Chinen T, Yoshida R, Okamoto F, Hanada T, Torisu K, Takaesu G, Kobayashi T, Yasukawa H, Yoshimura A
  • 雑誌名: Hepatology 47(5) ページ: 1644-1654
• [雑誌論文] Loss of Suppressor of Cytokine Signaling 1 in Helper T Cells Leads to Defective Th17 Differentiation by Enhancing Antagonistic Effects of IFN-{gamma} on STAT3 and Smads. (2008)
  • 著者名/発表者名: Tanaka K, Ichiyama K, Hashimoto M, Yoshida H, Takimoto T, Takaesu G, Torisu T, Hanada T, Yasukawa H, Fukuyama S, Inoue H, Nakanishi Y, Kobayashi T, Yoshimura A
  • 雑誌名: J Immunol 180(6) ページ: 3746-3756
• [雑誌論文] SOCS1 is an inducible host factor during HIV-1 infection and regulates the intracellular trafficking and stability of HIV-1 Gag. (2008)
  • 著者名/発表者名: Ryo A, Tsurutani N, Ohba K, Kimura R, Komano J, Nishi M, Soeda H, Hattori S, Perrem K, Yamamoto M, Chiba J, Mimaya J, Yoshimura K, Matsushita S, Honda M, Yoshimura A, Sawasaki T, Aoki I, Morikawa Y, Yamamoto N
  • 雑誌名: Proc Natl Acad Sci U S A 105(1) ページ: 294-299
• [雑誌論文] FLN29 deficiency reveals its negative regulatory role in the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like helicases signaling pathway (2008)
  • 著者名/発表者名: Sanada T, Takaesu G, Yoshida R, Kobayashi T, et.al.
  • 雑誌名: Journal of Biological Chemistry 283 ページ: 33858-33864
  • 査読あり
• [雑誌論文] Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat (2008)
  • 著者名/発表者名: Ichiyama K, Chinen, T, Kobayashi T, et.al.
  • 雑誌名: J Biological Chemistry 283 ページ: 10773-10778
  • 査読あり
• [雑誌論文] SOCS1 protects mice against concanavalin-A-induced hepatitis by inhibiting Fas, STAT1 and JNK-mediated apoptosis (2008)
  • 著者名/発表者名: Torisu T, Chinen T, Yasukawa H. Kobayashi T, et.al.
  • 雑誌名: Hepatology 47 ページ: 1644-1654
  • 査読あり
• [雑誌論文] FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging (2008)
  • 著者名/発表者名: Miyamoto K, Miyamoto T, Kato R
  • 雑誌名: Blood 112 ページ: 4485-4493
  • 査読あり
• [雑誌論文] Loss of Suppressor of Cytokine Signaling 1 in Helper T Cells Leads to Defective Th17 Differentiation by Enhancing Antagonistic Effects of IFN-{gamma} on STAT3 and Smads. (2008)
  • 著者名/発表者名: Tanaka, K・Kobayashi, T・Yoshimura, A, et. al.
  • 雑誌名: J Immunol. 180 ページ: 3746-56
  • 査読あり
• [雑誌論文] SOCS1 is an inducible host factor during HIV-1 infection and regulates the intracellualt trafficking and stability of HIV-1 Gag. (2008)
  • 著者名/発表者名: Ryo, A・Yoshimura, A・Aoki, I・Morikawa, Y・Yamamoto, N., et. al.
  • 雑誌名: Porc Natl Acad Sci USA. 105 ページ: 294-9
  • 査読あり
• [雑誌論文] SOCS proteins, cytokine signalling and immune regulation. (2007)
  • 著者名/発表者名: Yoshimura A, Naka T, Kubo M
  • 雑誌名: Nat Rev Immunol 7(6) ページ: 454-465
• [雑誌論文] Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. (2007)
  • 著者名/発表者名: Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A, Legius E
  • 雑誌名: Nature Genet 39(9) ページ: 1120-1126
• [雑誌論文] Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling. (2007)
  • 著者名/発表者名: Taniguchi K, Kohno R, Ayada T, Kato R, Ichiyama K, Morisada T, Oike Y, Yonemitsu Y, Maehara Y, Yoshimura A
  • 雑誌名: Mol Cell Biol. 27(12) ページ: 4541-4550
• [雑誌論文] Germline loss-of-function mutations in SPRED1 cause a neuofibromatosis 1-like phenotype. (2007)
  • 著者名/発表者名: Brems, H・Marynen, P・Thomas, G・Yoshimura, A・Legius, E, et. al.
  • 雑誌名: Nature Genet. 39 ページ: 1120-6
  • 査読あり
• [雑誌論文] Selective expansion of foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokin signaling 3-deficient dendritic cells. (2007)
  • 著者名/発表者名: Matsumura, Y・Wyss-Coray, T・Sato, K・Yoshimura, A, et. al.
  • 雑誌名: J Immunol. 179 ページ: 2170-9
  • 査読あり
• [雑誌論文] SOCS3 Protein Developmentally Regulates the Chemokine Receptor CXCR4-FAK Signaling Pathway during B Lymphopoiesis. (2007)
  • 著者名/発表者名: Le, Y・Yoshimura, A・Silberstein, LE, et. al.
  • 雑誌名: Immunity. 27 ページ: 811-823
  • 査読あり
• [雑誌論文] SOCS proteins, cytokine signalling and immune regulation. (2007)
  • 著者名/発表者名: Yoshimura, A・Naka, T・Kubo, M
  • 雑誌名: Nat Rev Immunol. 7 ページ: 454-65
  • 査読あり
• [雑誌論文] Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling. (2007)
  • 著者名/発表者名: Taniguchi, K・Maehara, Y・Yoshimura, A., et. al.
  • 雑誌名: Mol Cell Biol 27 ページ: 4541-50
  • 査読あり
• [雑誌論文] Sprouty2 and Sprouty4 are essential for embryonic morphogenesis and regulation of FGF signaling. (2007)
  • 著者名/発表者名: Taniguchi K, Ayada T, Ichiyama K, Yoshimura A, et al.
  • 雑誌名: Biochem Biophys Res Commun. 352(4) ページ: 896-902
• [雑誌論文] IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. (2006)
  • 著者名/発表者名: Hanada T, Kobayashi T, Chinen T, Saeki K, Takaki H, Koga K, Minoda Y, Sanada T, Yoshioka T, Mimata H, Kato S, Yoshimura A
  • 雑誌名: J Exp Med. 203(6) ページ: 1391-1397
• [雑誌論文] Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. (2006)
  • 著者名/発表者名: Ogata H, Kobayashi T, Chinen T, Takaki H, Sanada T, Minoda Y, Koga K, Takaesu G, Maehara Y, Iida M, Yoshimura A
  • 雑誌名: Gastroenterology 131(1) ページ: 179-193
• [雑誌論文] Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors. (2006)
  • 著者名/発表者名: Yoshida T, Hisamoto T, Akiba J, Koga H, Nakamura K, Tokunaga Y, Hanada S, Kumemura H, Maeyama M, Harada M, Ogata H, Yano H, Kojiro M, Ueno T, Yoshimura A, Sata M
  • 雑誌名: Oncogene 25(45) ページ: 6056-6066
• [雑誌論文] Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. (2006)
  • 著者名/発表者名: Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T, Ishii K, Yamane J, Yoshimura A, Iwamoto Y, Toyama Y, Okano H
  • 雑誌名: Nature Med. 12(7) ページ: 829-834
• [雑誌論文] Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-beta 1. (2006)
  • 著者名/発表者名: Kinjyo I, Inoue H, Hamano S, Fukuyama S, Yoshimura T, Koga K, Takaki H, Himeno K, Takaesu G, Kobayashi T, Yoshimura A
  • 雑誌名: J Exp Med. 203(4) ページ: 1021-1031
• [雑誌論文] Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-beta1 production. (2006)
  • 著者名/発表者名: Ogata H, Chinen T, Yoshida T, Kinjyo I, Takaesu G, Shiraishi H, Iida M, Kobayashi T, Yoshimura A
  • 雑誌名: Oncogene 25(17) ページ: 2520-2530
• [雑誌論文] Loss of SOCS3 gene expression converts STAT3 function from anti-apoptotic to pro-apoptotic. (2006)
  • 著者名/発表者名: Lu Y, Fukuyama S, Yoshida R, Yoshimura A, Takaesu G, et al.
  • 雑誌名: J Biol Chem. 281(48) ページ: 36683-36690
• [雑誌論文] TGF-beta1 suppresses IFN-gamma-induced NO production in macrophages by suppressing STAT1 activation and accelerating iNOS protein degradation. (2006)
  • 著者名/発表者名: Takaki H, Minoda Y, Yoshimura A, Kobayashi T, et al.
  • 雑誌名: Genes Cells. 11(8) ページ: 871-882
• [雑誌論文] Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. (2006)
  • 著者名/発表者名: Ogata H, Kobayashi T, Chinen T, Takaki H, Yoshimura A, et al.
  • 雑誌名: Gastroenterology. 131(1) ページ: 179-193
• [雑誌論文] IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. (2006)
  • 著者名/発表者名: Hanada T, Kobayashi T, Chinen T, Saeki K, Yoshimura A, et al.
  • 雑誌名: J Exp Med. 203(6) ページ: 1391-1397
• [雑誌論文] Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors. (2006)
  • 著者名/発表者名: Yoshida T, Hisamoto T, Akiba J, Yoshimura A, Sata M, et al.
  • 雑誌名: Oncogene. 25(45) ページ: 6056-6066
• [雑誌論文] Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-betal production. (2006)
  • 著者名/発表者名: Ogata H, Chinen T, Yoshida T, Yoshimura A, et al.
  • 雑誌名: Oncogene. (in press)
• [雑誌論文] Suppressor of Cytokine Signaling-1 Regulates Inflammatory Bowel Disease in Which Both IFNgamma and IL-4 Are Involved. (2006)
  • 著者名/発表者名: Chinen T, Kobayashi T, Ogata H, Yoshimura A, et al.
  • 雑誌名: Gastroenterology. 130(2) ページ: 373-388
• [雑誌論文] Suppressor of cytokine signalling 1 in lymphocytes regulates the development of intestinal inflammation in mice. (2006)
  • 著者名/発表者名: Inagaki-Ohara K, Sasaki A, Matsuzaki G, Yoshimura A, et al.
  • 雑誌名: Gut. 55(2) ページ: 212-219
• [雑誌論文] The Sprouty-related protein, Spred-1, localizes in a lipid raft/caveola and inhibits ERK activation in collaboration with caveolin-1. (2005)
  • 著者名/発表者名: Nonami A, Taketomi T, Kimura A, Yoshimura A, et al.
  • 雑誌名: Genes Cells. 10(9) ページ: 887-895
• [雑誌論文] Loss of mammalian Sprouty2 leads to enteric neuronal hyperplasia and esophageal achalasia. (2005)
  • 著者名/発表者名: Taketomi T, Yoshiga D, Taniguchi K, Yoshimura A, et al.
  • 雑誌名: Nat Neurosci. 8(7) ページ: 855-857
• [雑誌論文] Induction of hyper Th1 cell-type immune responses by dendritic cells lacking the suppressor of cytokine signaling-1 gene. (2005)
  • 著者名/発表者名: Hanada T, Tanaka K, Yoshimura A, et al.
  • 雑誌名: J Immunol. 174(7) ページ: 4325-4332
• [学会発表] SOCS is a molecular link between inflammation and cancer development. International symposium of infection-associated cancers (2010)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: Conference Hall of Hokkaido University in Sapporo
  • 発表場所: Hokkaido, Japan
• [学会発表] Role of SOCS1 in innate and adaptive immune tolerance (2010)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: World Immune Regulation Meeting IV
  • 発表場所: Davos Switzerland
• [学会発表] sponsored by Aegean ConferencesAldeamar Knossos Royal Village in Hersonissos (2009)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: Molecular basis for immune suppression by TGFb/Smad2/3 5th Leukocyte Signal Transduction Workshop
  • 発表場所: Crete, Greece
• [学会発表] SOCS1 and SOCS3 are Critical Regulators of Cytokine Signaling; Implication for Helper T Cell Differentiation and Tumor Development. (2007)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: Implication for Helper T Cell Differentiation and Tumor Development
  • 発表場所: KEYSTONE SYMPOSIA on Molecular and Cellular Biology Keystone USA
• [学会発表] SOCS1 is a link between inflammation and inflammation-mediated carcinogenesis. (2007)
  • 著者名/発表者名: Akihiko Yoshimura
  • 学会等名: 5th International Aachen Symposium on Cytokine Signalling
  • 発表場所: Aachen Germany
• [備考]
  • URL: http://www.new.immunoreg.jp/
• [備考]
  • URL: http://www.immunoreg.jp/