The role of gap junctional intercellular communication in NASH and its-related hepatocarcinogenesis

• Project/Area Number: 26460492
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nagoya City University
• Principal Investigator: NAIKI-ITO Aya 名古屋市立大学, 大学院医学研究科, 講師 (20509236)
• Co-Investigator(Kenkyū-buntansha): 高橋 智 名古屋市立大学, 大学院医学研究科, 教授 (60254281) ; 鈴木 周五 名古屋市立大学, 大学院医学研究科, 研究員 (60363933)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: NASH / 細胞間コミュニケーション / 疾患モデル / フラボノイド / 肝発がん

Outline of Final Research Achievements

NASH has the potential to lead to the development of cirrhosis and hepatocellular carcinoma (HCC). To clarify the role of hepatocyte gap junction protein, Cx32 and luteolin on the progression of NASH and hepatocarcinogenesis, Cx32 dominant negative transgenic (Tg) were used. Steatohepatitis, fibrosis, inflammatory cytokine expression, reactive oxygen species and number of preneoplastic foci were greater in Tg as compared with Wt rats, and significantly suppressed by luteolin in both genotypes. Microarray analysis identified Bex1 as an up-regulated gene in Tg rat liver. in situ hybridization revealed that increased Bex1 mRNA was localized in preneoplastic foci in Tg rats. Moreover, Bex1 increased cell proliferation through activation of NF-κB signaling in rat hepatocyte and HCC cell lines. These results show that Cx32 and luteolin have suppressive roles in inflammation, fibrosis and hepatocarcinogenesis during NASH progression, suggesting a potential therapeutic application for NASH.

Research Products

• [Journal Article] Dysfunction of gap-junctional intercellular communication promotes hepatocarcinogenesis (2016)
  • Author(s): Naiki-Ito A, Kato H, Sato S, Suzuki S, Yamashita Y, Kuno T, Takahashi S
  • Journal Title: 現代医学 Volume: 64 Pages: 103-108
• [Journal Article] Pioglitazone, a Peroxisome Proliferator-Activated Receptor γ Agonist, Suppresses Rat Prostate Carcinogenesis (2016)
  • Author(s): Suzuki S, Mori Y, Nagano A, Naiki-Ito A, Kato H, Nagayasu Y, Kobayashi M, Kuno T, Takahashi S
  • Journal Title: Int J Mol Sci Volume: 17 Issue: 12 Pages: 2071-2071
  • DOI: 10.3390/ijms17122071
  • Peer Reviewed / Open Access
• [Journal Article] Histone deacetylase inhibition in prostate cancer triggers miR-320-mediated suppression of the androgen receptor. (2016)
  • Author(s): Sato S, Katsushima K, Shinjo K, Hatanaka A, Ohka F, Suzuki S, Naiki-Ito A, Soga N, Takahashi S, Kondo Y.
  • Journal Title: Cancer Res. Volume: 76 Issue: 14 Pages: 4192-204
  • DOI: 10.1158/0008-5472.can-15-3339
  • Peer Reviewed / Open Access
• [Journal Article] Preventive effects of fermented brown rice and rice bran against prostate carcinogenesis in TRAP rats (2016)
  • Author(s): 4.Kuno T, Nagano A, Mori Y, Kato H, Nagayasu Y, Naiki-Ito A, Suzuki S, Mori H, Takahashi S
  • Journal Title: Nutrients Volume: 8 Issue: 7 Pages: 421-421
  • DOI: 10.3390/nu8070421
  • Peer Reviewed / Open Access
• [Journal Article] Connexin 32 dysfunction promotes ethanol-related hepatocarcinogenesis via activation of Dusp1-Erk axis. (2016)
  • Author(s): Kato H, Naiki-Ito A, Naiki T, Suzuki S, Yamashita Y, Sato S, Sagawa H, Kato A, Kuno T, Takahashi S.
  • Journal Title: Oncotarget. Volume: 7 Issue: 2 Pages: 2009-2021
  • DOI: 10.18632/oncotarget.6511
  • Peer Reviewed / Open Access
• [Journal Article] Chemopreventive effect of resveratrol and apocynin on pancreatic carcinogenesis via modulation of nuclear phosphorylated GSK3β and ERK1/2 (2015)
  • Author(s): Kato A, Naiki-Ito A, Nakazawa T, Hayashi K, Naitoh I, Miyabe K, Shimizu S, Kondo H, Nishi Y, Yoshida M, Umemura S, Hori Y, Mori T, Tsutsumi M, Kuno T, Suzuki S, Kato H, Ohara H, Joh T, Takahashi S
  • Journal Title: Oncotarget Volume: 6 Issue: 40 Pages: 42963-42975
  • DOI: 10.18632/oncotarget.5981
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Connexin 32 and luteolin play protective roles in non-alcoholic steatohepatitis development and its related hepatocarcinogenesis in rats. (2015)
  • Author(s): Sagawa H, Naiki-Ito A, Kato H, Naiki T, Yamashita Y, Suzuki S, Sato S, Shiomi K, Kato A, Kuno T, Matsuo Y, Kimura M, Takeyama H, Takahashi S.
  • Journal Title: Carcinogenesis Volume: 36 Pages: 1539-49
  • DOI: 10.1093/carcin/bgv143
  • Peer Reviewed / Open Access
• [Journal Article] Ellagic acid, a component of pomegranate fruit juice, suppresses androgen-dependent prostate carcinogenesis via induction of apoptosis (2015)
  • Author(s): Naiki-Ito A, Chewonarin T, Tang M, Pitchakarn P, Kuno T, Ogawa K, Asamoto M, Shirai T, Takahashi S
  • Journal Title: Prostate Volume: 75 Issue: 2 Pages: 151-160
  • DOI: 10.1002/pros.22900
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] NCL1, a highly selective lysine-specific demethylase 1 inhibitor, suppresses prostate cancer without adverse effect (2015)
  • Author(s): Etani T, Suzuki T, Naiki T, Naiki-Ito A, Ando R, Iida K, Kawai N, Tozawa K, Miyata N, Kohri K, Takahashi S
  • Journal Title: Oncotarget Volume: 6 Pages: 2865-2878
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] GPX2 overexpression is involved in cell proliferation and prognosis of castration resistant prostate cancer. (2014)
  • Author(s): Naiki, T., Naiki-Ito, A., Asamoto, M., Kawai, N., Tozawa, K., Etani, T., Sato, S., Suzuki, S., Shirai, T., Kohri, K., Takahashi, S.
  • Journal Title: Carcinogenesis Volume: in press Issue: 9 Pages: 1962-1967
  • DOI: 10.1093/carcin/bgu048
  • Peer Reviewed
• [Journal Article] Napsin A is a specific marker for ovarian clear cell adenocarcinoma. (2014)
  • Author(s): Yamashita Y, Nagasaka T, Naiki-Ito A, Sato S, Suzuki S, Toyokuni S, Ito M, Takahashi S.
  • Journal Title: Mod Pathol Volume: Apr 11 Issue: 1 Pages: 111-7
  • DOI: 10.1038/modpathol.2014.61
  • Peer Reviewed
• [Presentation] Chemotherapeutic effect of luteolin on castration-resistant prostate cancer (2016)
  • Author(s): Aya Naiki-Ito, Taku Naiki, Hiroyuki Kato, Shugo Suzuki, Yoriko Yamashita, Toshiya Kuno, Satoru Takahashi
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] 去勢抵抗性前立腺癌に対するluteolinの治療効果 (2016)
  • Author(s): 内木綾、加藤寛之、佐藤慎哉、鈴木周五、山下依子、久野壽也、髙橋智
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-05-12
• [Presentation] 前立腺発がんおよび去勢抵抗性細胞増殖に対するluteolinの抑制効果 (2015)
  • Author(s): 内木 綾、内木 拓、加藤 寛之、惠谷 俊紀、佐藤 慎哉、鈴木 周五、安井 孝周、高橋 智
  • Organizer: 前立腺シンポジウム
  • Place of Presentation: 東京コンファレンスセンター（東京都港区）
  • Year and Date: 2015-12-12
  • Invited
• [Presentation] ラット非アルコール性脂肪肝炎および肝発がんにおけるconnexin 32の役割とluteolinによる予防効果 (2015)
  • Author(s): 内木 綾、加藤 寛之、久野 壽也、高橋 智
  • Organizer: 発癌病理研究会
  • Place of Presentation: オリビアン小豆島（香川県小豆郡）
  • Year and Date: 2015-08-26
• [Presentation] Connexin 32機能低下状態におけるアルコールのラット肝発がん促進作用 (2015)
  • Author(s): 加藤 寛之、内木 綾、久野 壽也、高橋 智
  • Organizer: 第31回日本毒性病理学会総会
  • Place of Presentation: タワーホール船堀・東京都（江戸川区）
  • Year and Date: 2015-01-29 – 2015-01-30
• [Presentation] Chemopreventive effect of connexin 32 and luteolin on non-alcoholic steatohepatitis and hepatocarcinogenesis in rats (2014)
  • Author(s): Aya Naiki-Ito, Hiroyuki Sagawa, Hiroyuki Kato, Yoriko Yamashita, Toshiya Kuno, Shugo Suzuki, Hiromitsu Takeyama, Satoru Takahashi
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜・神奈川県（横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Ethanol promote diethylnitrosamine-induced hepatocarcinogenesis in connexin 32 dominant negative rats (2014)
  • Author(s): Hiroyuki Kato, Aya Naiki-Ito, Shugo Suzuki, Misawo Ishikawa, Satoru Takahashi
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜・神奈川県（横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Remarks] 増え続ける新たな肝癌リスク「非アルコール性脂肪肝炎」 予防に「エゴマ成分」が有効
  • URL: http://www.nagoya-cu.ac.jp/about/press/press/release/files/169397/271023.pdf