Novel roles of chronic inflammatory factor CYLD in lung fibrosis

• Project/Area Number: 23790091
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Kumamoto University
• Principal Investigator: JONO Hirofumi 熊本大学, 医学部附属病院, 准教授 (40515483)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肺線維症 / CYLD / 慢性炎症 / TGF / 腫瘍抑制遺伝子 / 脱ユビキチン化酵素

Research Abstract

Lung Fibrosis, a fatal progressive pathological condition caused by chronic inflammation, is deeply-involved in the pathogenesis of various kinds of pulmonary diseases. In this study, we focused on CYLD, a novel chronic inflammatory factor, and elucidated the molecular pathogenesis of lung fibrosis. We revealed that, 1. Loss of CYLD promoted lung fibrosis via overproduction of fibrotic response gene, 2. Loss of CYLD caused overproduction of fibrotic response gene via increasing Smad3 protein expression by suppressing Smad3 degradation. Those results suggest that CYLD regulates the fibrotic response gene expressopn and plays important roles in the molecular pathogenesis of lung fibrosis.

Research Products

• [Journal Article] Clinical Significance of CYLD Downregulation in Breast Cancer (2014)
  • Author(s): Hayashi M, Jono H, Shinriki S, Nakamura T, Guo J, Sueta A, Tomiguchi M, Fujiwara S, Yamamoto-Ibusuki M, Murakami K, Yamashita S, Yamamoto Y, Li J-D, Iwase H, Ando Y.
  • Journal Title: Breast Cancer Res. Treat Volume: (in press)
  • Peer Reviewed
• [Journal Article] Stromal Expression of Neutrophil Gelatinase-Associated Lipocalin Correlates with Poor Differentiation and Adverse Prognosis in Oral Squamous Cell Carcinoma (2014)
  • Author(s): Shinriki S, Jono H , Ueda M, Obayashi K, Nakamura T, Ota K, Ota T, Sueyoshi T, Guo J, Hayashi M, Hiraki A, Nakayama H, Yamashita S, Shinohara M, Ando Y
  • Journal Title: Histopathology Volume: 64 Pages: 356-64
  • Peer Reviewed
• [Journal Article] Stromal Expression of Neutrophil Gelatinase-Associated Lipocalin Correlates with Poor Differentiation and Adverse Prognosis in Oral Squamous Cell Carcinoma. (2014)
  • Author(s): Shinriki S, Jono H, Ueda M, Obayashi K, Nakamura T, Ota K, Ota T, Sueyoshi T, Guo J, Hayashi M, Hiraki A, Nakayama H, Yamashita S, Shinohara M, Ando Y.
  • Journal Title: Histopathology Volume: 64 Pages: 356-364
  • Peer Reviewed
• [Journal Article] Clinical significance of CYLD downregulation in breast cancer. (2014)
  • Author(s): Hayashi M, Jono H, Shinriki S, Nakamura T, Guo J, Sueta A, Tomiguchi M, Fujiwara S, Yamamoto-Ibusuki M, Murakami K, Yamashita S, Yamamoto Y, Li JD, Iwase H, Ando Y.
  • Journal Title: Breast Cancer Res Treat. Volume: 143 Issue: 3 Pages: 447-457
  • DOI: 10.1007/s10549-013-2824-3
  • Peer Reviewed
• [Journal Article] CYLD down-regulation is correlated with tumor development in patients with hepatocellular carcinoma (2013)
  • Author(s): Kinoshita H, Okabe H, Beppu T, Chikamoto A, Hayashi H, Imai K, Mima K, Nakagawa S, Yokoyama N, Ishiko T, Shinriki S, Jono H, Ando Y, Baba H
  • Journal Title: Molecular and Clinical Oncology Pages: 309-314
  • Peer Reviewed
• [Journal Article] Suppression of inflammation via PDE4B-JNK2-dependent upregulation of deubiquitinase CYLD (2013)
  • Author(s): Komatsu K, Lee J, Miyata M, Lim JH, Jono H, Koga T, Xu H, Yan C, Kai H, Li JD
  • Journal Title: Nature Commun Volume: 4 Pages: 1684-1684
  • Peer Reviewed
• [Journal Article] CYLD downregulation is correlated with tumor development in patients with hepatocellular carcinoma. (2013)
  • Author(s): Kinoshita H, Okabe H, Beppu T, Chikamoto A, Hayashi H, Imai K, Mima K, Nakagawa S, Yokoyama N, Ishiko T, Shinriki S, Jono H, Ando Y, Baba H
  • Journal Title: Mol Clin Oncol. Volume: 1 Pages: 309-314
  • Peer Reviewed
• [Journal Article] Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD (2013)
  • Author(s): Komatsu K
  • Journal Title: Nature Communications Volume: 4 Issue: 1 Pages: 1684-1684
  • DOI: 10.1038/ncomms2674
  • Peer Reviewed
• [Journal Article] PDE4B mediates ERK dependent up-regulation of mucin MUC5AC by S. pneumoniae by inhibiting cAMP-PKA dependent MKP-1 pathway (2012)
  • Author(s): Lee J, Komatsu K, Lee BC, Lim JH, Jono H, Xu H, Kai H, Zhang ZJ, Yan C, Li JD
  • Journal Title: J Biol Chem Volume: 287 Pages: 22799-811
  • Peer Reviewed
• [Journal Article] CYLD Negatively Regulates Transforming Growth Factor-B Signaling via Deubiquitinating Akt (2012)
  • Author(s): Lim JH, Jono H, Komatsu K, Dr. Woo CH, Lee J, Miyata M, Matsuno T, Xu X, Huang Y, Zhang W, Park SH, Kim YI, Choi YD, Shen H, Heo KS, Xu H, Bourne P, Koga T, Xu H, Yan C, Wang B, Chen LF, Feng XH, Li JD
  • Journal Title: Nature Commun Volume: 3 Pages: 771-771
  • Peer Reviewed
• [Journal Article] Identification of CXCL5/ENA-78 as a factor involved in the interaction between cholangiocarcinoma cells and cancer-associated fibroblasts (2012)
  • Author(s): Okabe H, Beppu T, Ueda M, Hayashi H, Ishiko T, Masuda T, Otao R, Horlad H, Mima K, Miyake K, Iwatsuki M, Baba Y, Takamori H, Jono H, Shinriki S, Ando Y, Baba H
  • Journal Title: Int J Cancer Volume: 131 Pages: 2234-41
  • Peer Reviewed
• [Journal Article] Downregulation of midkine induces cisplatin resistance in human oral squamous cell carcinoma (2012)
  • Author(s): Ota T, Jono H, Ota K, Shinriki S, Ueda M, Sueyoshi T, Nakatani K, Fujita S, Obayashi K, Shinohara M, Ando Y
  • Journal Title: Oncology Reports Volume: 27 Pages: 1674-80
  • Peer Reviewed
• [Journal Article] PKCθsynergizes with TLR-dependent TRAF6 signaling pathway to upregulate MUC5AC mucin via CARMA1 (2012)
  • Author(s): Jono H, Lim JH, Xu H, Li JD
  • Journal Title: PLoS ONE Volume: 7 Pages: 31049-31049
  • Peer Reviewed
• [Journal Article] Therapeutic approaches targeting midkine suppress tumor growth and lung metastasis in osteosarcoma (2012)
  • Author(s): Sueyoshi T, Jono H, Shinriki S, Ota K, Ota T, Tasaki M, Atsuyama E, Yakushiji T, Ueda M, Obayashi K, Mizuta H, Ando Y
  • Journal Title: Cancer Lett Volume: 316 Pages: 23-30
  • Peer Reviewed
• [Journal Article] Phosphodiesterase 4B Mediates Extracellular Signal-regulated Kinase-dependent Up-regulation of Mucin MUC5AC Protein by Streptococcus pneumoniae by Inhibiting cAMP-protein Kinase A-dependent MKP-1 Phosphatase Pathway. (2012)
  • Author(s): Lee J
  • Journal Title: J Biol Chem. Volume: 287 Issue: 27 Pages: 22799-22811
  • DOI: 10.1074/jbc.m111.337378
  • Peer Reviewed
• [Journal Article] CYLD Negatively Regulates Transforming Growth Factor-B Signaling via Deubiquitinating Akt. (2012)
  • Author(s): Lim JH, Jono H, Komatsu K, Woo CH, Lee J, Miyata M, Matsuno T, Xu X, Huang Y, Zhang W, et al.
  • Journal Title: Nature Communications Volume: 3 Issue: 1 Pages: 771-771
  • DOI: 10.1038/ncomms1776
  • Peer Reviewed
• [Journal Article] Identification of CXCL5/ENA-78 as afactor involved in the interactionbetween cholangiocarcinoma cells andcancer-associated fibroblasts. (2012)
  • Author(s): Okabe H, Beppu T, Ueda M, Hayashi H,Ishiko T, Masuda T, Otao R, Horlad H,Mima K, Miyake K, Iwatsuki M, Baba Y,Takamori H, Jono H, Shinriki S, AndoY, Baba H
  • Journal Title: Int J Cancer 131 Volume: in press Issue: 10 Pages: 2234-41
  • DOI: 10.1002/ijc.27496
  • Peer Reviewed
• [Journal Article] Long-term survival after liver transplantation in patients with familial amyloid polyneuropathy (2012)
  • Author(s): Yamashita T
  • Journal Title: Neurology Volume: 78 Pages: 637-43
  • DOI: 10.3892/or.2012.1684
  • Peer Reviewed
• [Journal Article] PKCθ synergizes with TLR-dependent TRAF6 signaling pathway to upregulate MUC5AC mucin via CARMA1 (2012)
  • Author(s): Jono H, Lim JH, Xu H, Li JD.
  • Journal Title: PLoS One Volume: 7 Issue: 1 Pages: e31049-e31049
  • DOI: 10.1371/journal.pone.0031049
  • Peer Reviewed
• [Journal Article] Therapeutic approaches targeting midkine suppress tumor growth and lung metastasis in osteosarcoma. (2012)
  • Author(s): Takanao Sueyoshi, Hirofumi Jono, Satoru Shinriki, Kazutoshi Ota, Tomoko Ota, Masayoshi Tasaki, Eri Atsuyama, Toshitake Yakushiji, Mitsuharu Ueda, Konen Obayashi, Hiroshi Mizuta, Yukio Ando
  • Journal Title: Cancer Letter Volume: Volume 316, Issue 1 Issue: 1 Pages: 23-30
  • DOI: 10.1016/j.canlet.2011.10.013
  • NAID: 120004419579
  • Peer Reviewed
• [Journal Article] Effects of a Novel Nonantibiotic Macrolide,EM900, on Cytokine and Mucin Gene Expression in a Human Airway Epithelial Cell Line (2011)
  • Author(s): Otsu K, Ishinaga H, Suzuki S, Sugawara A, Sunazuka T, Omura S, Jono H, Takeuchi K
  • Journal Title: Pharmacology Volume: 88 Pages: 327-332
  • Peer Reviewed
• [Journal Article] Hepatic Stellate Cells Accelerate the Malignant Behavior of Cholangiocarcinoma Cells (2011)
  • Author(s): Okabe H, Beppu T, Hayashi H, Ishiko T, Masuda T, Otao R, Horlad H, Jono H, Ueda M, Phd SS, Ando Y, Baba H
  • Journal Title: Ann Surg Oncol Volume: 18 Pages: 1175-1184
  • Peer Reviewed
• [Journal Article] Effects of a novel nonantibiotic macrolide, EM900, on cytokine and mucin gene expression in a human airway epithelial cell line. (2011)
  • Author(s): Otsu K, Ishinaga H, Suzuki S, Sugawara A, Sunazuka T, Omura S, Jono H, Takeuchi K.
  • Journal Title: Pharmacology Volume: 88 Issue: 5-6 Pages: 327-32
  • DOI: 10.1159/000334339
  • Peer Reviewed
• [Presentation] Signal transduction mechanisms and their tight regulation in nontypeable Haemophilus influenzae (2013)
  • Author(s): Jono H
  • Organizer: infection 2013 International Meeting of the Microbiological Society of Korea
  • Place of Presentation: Jeonju city, Korea
  • Year and Date: 2013-05-01
• [Presentation] Uncovering host epithelial signaling networks by respiratory bacterial pathogens (2013)
  • Author(s): Jono H
  • Organizer: World-Class University & 5th microbial pathogenesis & immunity symposium
  • Place of Presentation: Su-Won, Korea
  • Year and Date: 2013-04-30
• [Presentation] Loss of CYLD promotes cell migration through stabilized ALK5 in human oral squamous cell (2013)
  • Author(s): Shinriki S, Jono H, Li J-D, Nakamura T, Hayashi M, Guo J, Shinohara M, Ando Y
  • Organizer: carcinoma AACR Annual meeting
  • Place of Presentation: Washington, USA
  • Year and Date: 2013-04-06
• [Presentation] 骨肉腫におけるがん抑制遺伝子CYLDの生物学的活性の解明 (2013)
  • Author(s): 城野博史、末吉貴直、神力悟、厚山恵里、柳澤哲大、薬師寺俊剛、田崎雅義、大林光念、水田博志、安東由喜雄
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 2013-03-27
• [Presentation] Loss of tumor suppressor CYLD triggers cell invasion of human oral squamous cell carcinoma cells (2013)
  • Author(s): 城野博史、神力悟、大林光念、安東由喜雄
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡国際会議場、福岡
  • Year and Date: 2013-03-21
• [Presentation] Uncovering host epithelial signaling networks by respiratory bacterial pathogens (2013)
  • Author(s): Hirofumi Jono
  • Organizer: World-Class University & The 5th microbial pathogenesis & immunity symposium
  • Place of Presentation: Su-Won, Korea
  • Invited
• [Presentation] Signal transduction mechanisms and their tight regulation in nontypeable Haemophilus influenzae infection (2013)
  • Author(s): Hirofumi Jono
  • Organizer: 2013 International Meeting of the Microbiological Society of Korea
  • Place of Presentation: Jeonju city, Korea
  • Invited
• [Presentation] Loss of CYLD promotes cell migration through stabilized ALK5 in human oral squamous cell carcinoma cells. (2013)
  • Author(s): Satoru Shinriki, Hirofumi Jono, Jian-Dong Li, Takuya Nakamura, Mitsuhiro Hayashi, Jianying Guo, Masanori Shinohara, Yukio Ando
  • Organizer: AACR Annual Meeting
  • Place of Presentation: Washington, USA
• [Presentation] Loss of tumor suppressor CYLD triggers cell invasion of human oral squamous cell carcinoma cells (2013)
  • Author(s): 城野博史
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡（福岡国際会議場）
• [Presentation] 骨肉腫におけるがん抑制遺伝子 CYLD の生物学的活性の解明 (2013)
  • Author(s): 城野博史
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜（パシフィコ横浜）
• [Presentation] 頭頸部扁平上皮癌におけるがん抑制遺伝子CYLD発現低下の臨床的意義の解 (2012)
  • Author(s): 城野博史、神力悟、大林光念、田崎雅義、安東由喜雄
  • Organizer: 第65回日本薬理学会西南部会
  • Place of Presentation: 熊本,熊本大学薬学部
  • Year and Date: 2012-11-23
• [Presentation] 骨肉腫進展におけるCYLDの関与と生物学的意義の解明 (2012)
  • Author(s): 城野博史、末吉貴直、神力悟、厚山恵里、柳澤哲大、薬師寺俊剛、田崎雅義、大林光念、水田博志、安東由喜雄
  • Organizer: 第52回臨床化学会年会
  • Place of Presentation: いわて県民情報交流センターアイーナ、盛岡
  • Year and Date: 2012-09-06
• [Presentation] 骨肉腫進展におけるCYLDの関与と生物学的意義の解明 (2012)
  • Author(s): 城野博史
  • Organizer: 第52回日本臨床化学会年次学術集会
  • Place of Presentation: 盛岡（いわて県民情報交流センター アイーナ）
• [Presentation] 頭頸部扁平上皮癌におけるがん抑制遺伝子CYLD発現低下の臨床的意義の解明 (2012)
  • Author(s): 城野博史
  • Organizer: 第65回日本薬理学会西南部会
  • Place of Presentation: 熊本（熊本大学薬学部）
• [Presentation] 低酸素環境における腫瘍抑制遺伝子cylincromatosis (CYLD)の発現異常 (2011)
  • Author(s): 郭建エイ,神力悟,城野博史,厚山恵理,太田和俊,太田智子,中村拓哉,大林光念,安東由喜雄
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場、愛知
  • Year and Date: 2011-10-03
• [Presentation] 低酸素環境における腫瘍抑制遺伝子cylincromatosis (CYLD)の発現異常 (2011)
  • Author(s): 津田幸元,神力悟,村上慶高,城野博史,安東由喜雄
  • Organizer: 第51回臨床化学会年会
  • Place of Presentation: 札幌医科大学、札幌
  • Year and Date: 2011-08-28
• [Presentation] Cylincromatosis(CYLD)発現低下は口腔扁上皮癌の血管新生を誘導する (2011)
  • Author(s): 村上慶高,神力悟,津田幸元,城野博史,安東由喜雄
  • Organizer: 第51回臨床化学会年会
  • Place of Presentation: 札幌医科大学、札幌
  • Year and Date: 2011-08-28
• [Presentation] 低酸素環境における腫瘍抑制遺伝子cylincromatosis (CYLD) の発現異常 (2011)
  • Author(s): 郭 建エイ, 神力 悟, 城野 博史, 厚山 恵理, 太田 和俊, 太田 智子, 中村 拓哉, 大林 光念, 安東 由喜雄
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 愛知県名古屋市 名古屋国際会議場
• [Presentation] 低酸素環境における腫瘍抑制遺伝子Cylincromatosis（CYLD）の発現異常 (2011)
  • Author(s): 津田幸元, 神力悟, 村上慶高, 城野博史, 安東由喜雄
  • Organizer: 第51回臨床化学会年会
  • Place of Presentation: 北海道札幌市 札幌医科大学
• [Presentation] Cylincromatosis（CYLD）発現低下は口腔扁上皮癌の血管新生を誘導する (2011)
  • Author(s): 村上慶高, 神力悟, 津田幸元, 城野博史, 安東由喜雄
  • Organizer: 第51回臨床化学会年会
  • Place of Presentation: 北海道札幌市 札幌医科大学
• [Remarks]
  • URL: http://www2.kuh.kumamoto-u.ac.jp/pharmacy/default.html