Analysis of carcinogenesis in hepatocellular carcinoma using Nrf2-p62 double knock out mouse

• Project/Area Number: 15H04917
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: University of Tsukuba
• Principal Investigator: YANAGAWA Toru 筑波大学, 医学医療系, 准教授 (10312852)
• Co-Investigator(Kenkyū-buntansha): 田渕 克彦 信州大学, 学術研究院医学系, 教授 (20546767) ; 蕨 栄治 筑波大学, 医学医療系, 講師 (70396612) ; 内田 文彦 筑波大学, 附属病院, 医員 (70736008)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2015: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: p62 / Nrf2 / ｐ62 / 肝臓癌 / 癌 / オートファジー / 肝細胞癌

Outline of Final Research Achievements

We generated Nrf2-p62 double knock out mouse. Nrf2 is a transcription factor against oxidative stress . p62 is a substrate of selective autophagy. The liver of this mouse showed at first NAFLD and NASH, then finally turn into hepatocellular carcinoma. We found p62 deficient MEF showed resistance to apoptosis. Nrf2-p62 DKO cell showed reduction of phagocytic capacity of hepatic Kupffer cell (macrophage). By using clinical samples, immunohistochemical analysis of p62、LC3-A・B expression in normal tissue with carcinoma was performed. The p62、LC3-A・B expression group showed significantly poor prognosis analyzed by Kaplan mere curve and log rank test. The LC3-A・B expression group showed significantly poor prognosis analyzed by Cox's proportional hazard regression model. From above results we discussed the cause of carcinogenesis of hepatocellular carcinoma by p62 deficiency and oxidative stress accumulation.

Research Products

• [Journal Article] Deletion of both <i>p62</i> and <i>Nrf2</i> spontaneously results in the development of nonalcoholic steatohepatitis (2018)
  • Author(s): AKIYAMA Kentaro、WARABI Eiji、OKADA Kosuke、YANAGAWA Toru、ISHII Tetsuro、KOSE Katsumi、TOKUSHIGE Katsutoshi、ISHIGE Kazunori、MIZOKAMI Yuji、YAMAGATA Kenji、ONIZAWA Kojiro、ARIIZUMI Shun-ichi、YAMAMOTO Masakazu、SHODA Junichi
  • Journal Title: Experimental Animals Volume: 67 Issue: 2 Pages: 201-218
  • DOI: 10.1538/expanim.17-0112
  • NAID: 130006733609
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access
• [Journal Article] Expression of autophagy-related markers at the surgical margin of oral squamous cell carcinoma correlates with poor prognosis and tumor recurrence (2018)
  • Author(s): Terabe Takehito、Uchida Fumihiko、Nagai Hiroki、Omori Shoei、Ishibashi-Kanno Naomi、Hasegawa Shogo、Yamagata Kenji、Gosho Masahiko、Yanagawa Toru、Bukawa Hiroki
  • Journal Title: Hum Pathol Volume: 73 Pages: 156-163
  • DOI: 10.1016/j.humpath.2017.11.019
  • Peer Reviewed
• [Journal Article] Synaptic-Adhesion Molecules Neurexin 1 and Neuroligin 1 as Novel Prognostic Factors in Oral Squamous Cell Carcinoma (2018)
  • Author(s): Hirohata H, Yanagawa T, Takaoka H, Uchida F, Shibuya Y, Miyabe S, Tabuchi K, Akagi Y, Hasegawa S, Sakai S, Takeuchi Y, Ishibashi-Kanno N,Yamagata K, Bukawa H.
  • Journal Title: J Dents Dent Med Volume: 2 Pages: 11-11
  • Peer Reviewed / Open Access
• [Journal Article] Corrigendum to "p62 modulates the intrinsic signaling of UVB-induced apoptosis" [Journal of Dermatological Science 83 (2016) 226-233]. (2017)
  • Author(s): Ito S, Kimura S, Warabi E, Kawachi Y, Yamatoji M, Uchida F, Ishibashi-Kanno N, Yamagata K, Hasegawa S, Shoda J, Tabuchi K, Sakai S, Bukawa H, Sekido M, Yanagawa T.
  • Journal Title: J Dermatol Sci Volume: 印刷中 Issue: 3 Pages: 259-260
  • DOI: 10.1016/j.jdermsci.2017.02.284
  • Peer Reviewed
• [Journal Article] p62 modulates the intrinsic signaling of UVB-induced apoptosis. (2016)
  • Author(s): Ito S, Kimura S, Warabi E, Kawachi Y, Yamatoji M, Uchida F, Ishibashi-Kanno N, Yamagata K, Hasegawa S, Shoda J, Tabuchi K, Sakai S, Bukawa H, Sekido M, Yanagawa T.
  • Journal Title: Journal of Dermatological Science Volume: 83 Issue: 3 Pages: 226-233
  • DOI: 10.1016/j.jdermsci.2016.05.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 外傷歯における生体のストレスとp62の機能 (2015)
  • Author(s): 柳川 徹
  • Journal Title: 日外傷歯誌 Volume: 11 Pages: 1-8
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 口腔白板症におけるp62の発現に関する病理組織学的検討 (2016)
  • Author(s): 長井宏樹 ほか
  • Organizer: 第60回（公社）日本口腔外科学会総会・学術大会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2016-04-16
• [Presentation] 口腔がん切除断端における酸化ストレス関連タンパク質p62/SQSTM1, LC3-A, LC-3Bの発現と腫瘍再発、生存率の関連性の検討 (2016)
  • Author(s): 寺邊 健人 ほか
  • Organizer: 第70回 NPO法人日本口腔科学会学術集会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2016-04-16
• [Presentation] 口腔がん切除断端における酸化ストレ ス関連タンパクp62/SQSTM1,LC3-A, LC3-Bの発現と腫瘍再発,生存率の関連 性の検討 (2016)
  • Author(s): 寺邊健人ほか
  • Organizer: 第 70 回 NPO 法人 日本口腔科学会学術集会
  • Place of Presentation: 福岡国際会議場・福岡県・福岡市
  • Year and Date: 2016-04-15
• [Presentation] p62 modulate intrinsic apoptosis signal of UVB induced skin cancer in head and neck region (2015)
  • Author(s): Sachiko Ito, et.al.
  • Organizer: 第39回頭頸部癌学会・第4回アジア頭頸部癌学会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-06-04
  • Int'l Joint Research