Elucidation of synergy in hepatocarcinogenesis by hepatitis B virus, inflammation and hypernutrition

• Project/Area Number: 15H04807
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: KOIKE KAZUHIKO 東京大学, 医学部附属病院, 教授 (80240703)
• Co-Investigator(Kenkyū-buntansha): 森屋 恭爾 東京大学, 医学部附属病院, 教授 (00272550) ; 堤 武也 東京大学, 医科学研究所, 准教授 (00726739)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2017: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2016: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
• Keywords: 肝癌 / B型肝炎 / 炎症 / ウイルス / 肥満 / 内科 / 肝発癌 / NASH / 脂肪肝

Outline of Final Research Achievements

Hepatitis B virus (HBV) infection can lead to cirrhosis and hepatocellular carcinoma. Episomal viral covalently closed circular DNA (cccDNA) minichromosomes and transcripts from cccDNA continue to be expressed over the long term. We showed that the host protein DExH-box helicase 9 (DXH9) is associated with viral RNAs. We also showed that viral-derived circular RNA is produced during HBV replication, and the amount is increased by knockdown of the DHX9 protein, which, in turn, results in decreased viral protein levels but does not affect the levels of HBV DNA. In addition, through a comprehensive compound screen using a newly constructed split luciferase system, we showed that nitazoxanide (NTZ) efficiently inhibits the HBx-DDB1 interaction. NTZ significantly restores Smc5 protein levels and suppresses viral transcription and viral protein production in the HBV minicircle system, in in vitro HBV replicating models, and in human primary hepatocytes naturally infected with HBV.

Research Products

• [Int'l Joint Research] Icahn School of Medicine at Mount Sinai(米国)
• [Int'l Joint Research] National University Health System(Singapore)
• [Int'l Joint Research] Xiamen University, Xiamen, Fujian(China)
• [Int'l Joint Research] The Scripps Research Institute(米国)
• [Int'l Joint Research] The University of Texas Medical School(米国)
• [Journal Article] DHX9 regulates production of hepatitis B virus-derived circular RNA and viral protein levels (2018)
  • Author(s): Sekiba K, Otsuka M, Ohno M, Kishikawa T, Yamagami M, Suzuki T, Ishibashi R, Seimiya T, Tanaka E, Koike K.
  • Journal Title: Oncotarget Volume: 9
  • Peer Reviewed / Open Access
• [Journal Article] Relationship of muscle cramps to quality of life and sleep disturbance in patients with chronic liver diseases: a nationwide study (2018)
  • Author(s): Iwasa Motoh、Karino Yoshiyasu、Kawaguchi Takumi、Nakanishi Hiroyuki、Miyaaki Hisamitsu、Shiraki Makoto、Nakajima Tomoaki、Sawada Yasuhiko、Yoshiji Hitoshi、Okita Kiwamu、Koike Kazuhiko
  • Journal Title: Liver International Volume: 38 Issue: 12 Pages: 2309-2316
  • DOI: 10.1111/liv.13745
  • Peer Reviewed / Open Access
• [Journal Article] CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity (2018)
  • Author(s): Fujiwara Naoto、Nakagawa Hayato、Enooku Kenichiro、Otsuka Motoyuki、Tateishi Keisuke、Koike Kazuhiko
  • Journal Title: Gut Volume: 67 Issue: 8 Pages: 1493-1504
  • DOI: 10.1136/gutjnl-2017-315193
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Response criteria of tolvaptan for the treatment of hepatic edema (2017)
  • Author(s): Hiramine Yasunari、Uojima Haruki、Nakanishi Hiroyuki、Hiramatsu Akira、Iwamoto Takuya、Kimura Mutsuumi、Kawaratani Hideto、Terai Shuji、Yoshiji Hitoshi、Uto Hirofumi、Sakaida Isao、Izumi Namiki、Okita Kiwamu、Koike Kazuhiko
  • Journal Title: Journal of Gastroenterology Volume: 53 Issue: 2 Pages: 258-268
  • DOI: 10.1007/s00535-017-1366-6
  • Peer Reviewed / Open Access
• [Journal Article] RASAL1 is a potent regulator of hepatic stellate cell activity and liver fibrosis (2017)
  • Author(s): Takata Akemi、Otsuka Motoyuki、Kishikawa Takahiro、Yamagami Mari、Ishibashi Rei、Sekiba Kazuma、Suzuki Tatsunori、Ohno Motoko、Yamashita Yui、Abe Takaya、Masuzaki Ryota、Ikenoue Tsuneo、Koike Kazuhiko
  • Journal Title: Oncotarget Volume: 8 Issue: 39 Pages: 64840-64852
  • DOI: 10.18632/oncotarget.17609
  • Peer Reviewed / Open Access
• [Journal Article] Randomized prospective study showing the non-inferiority of tenofovir to entecavir in treatment-na?ve chronic hepatitis B patients (2017)
  • Author(s): Koike Kazuhiko、Suyama Kazuaki、Ito Hiroshi、Itoh Hiroshi、Sugiura Wataru
  • Journal Title: Hepatology Research Volume: 48 Issue: 1 Pages: 59-68
  • DOI: 10.1111/hepr.12902
  • Peer Reviewed / Open Access
• [Journal Article] Mortality and hemorrhagic complications associated with radiofrequency ablation for treatment of hepatocellular carcinoma in patients on hemodialysis for end-stage renal disease: A nationwide survey. (2017)
  • Author(s): Sato M, Tateishi R, Yasunaga H, Matsui H, Horiguchi H, Fushimi K, Koike K.
  • Journal Title: J Gastroenterol Hepatol. Volume: 32 Issue: 11 Pages: 1873-1878
  • DOI: 10.1111/jgh.13780
  • Peer Reviewed / Open Access
• [Journal Article] Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands. (2017)
  • Author(s): Nakagawa H, Suzuki N, Hirata Y, Hikiba Y, Hayakawa Y, Kinoshita H, Ihara S, Uchino K, Nishikawa Y, Ijichi H, Otsuka M, Arita J, Sakamoto Y, Hasegawa K, Kokudo N, Tateishi K, Koike K.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114(19) Issue: 19
  • DOI: 10.1073/pnas.1619416114
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptional activation of the MICA gene with an engineered CRISPR-Cas9 system (2017)
  • Author(s): Sekiba K, Yamagami M, Otsuka M, Suzuki T, Kishikawa T, Ishibashi R, Ohno M, Sato M, Koike K
  • Journal Title: Biochem Biophys Res Commun Volume: - Issue: 2 Pages: 521-525
  • DOI: 10.1016/j.bbrc.2017.03.076
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells (2016)
  • Author(s): Umemura A, He F, Taniguchi K, Nakagawa H, Yamachika S, Font-Burgada J, Zhong Z, Subramaniam S, Raghunandan S, Duran A, Linares JF, Reina-Campos M, Umemura S, Valasek MA, Seki E, Yamaguchi K, Koike K, Itoh Y, Diaz-Meco MT, Moscat J, Karin M
  • Journal Title: Cancer Cell Volume: 29 Issue: 6 Pages: 935-948
  • DOI: 10.1016/j.ccell.2016.04.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutual antagonism between hepatitis B viral mRNA and host microRNA let-7. (2016)
  • Author(s): Takata A, Otsuka M, Ohno M, Kishikawa T, Yoshikawa T, Koike K.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 23237-23237
  • DOI: 10.1038/srep23237
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The intrahepatic expression levels of bile acid transporters are inversely correlated with the histological progression of nonalcoholic fatty liver disease (2016)
  • Author(s): Okushin K, Tsutsumi T, Enooku K, Fujinaga H, Kado A, Shibahara J, Fukayama M, Moriya K, Yotsuyanagi H, Koike K
  • Journal Title: J Gastroenterol Volume: 51 Issue: 8 Pages: 808-818
  • DOI: 10.1007/s00535-015-1148-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Higher LPA2 and LPA6 mRNA Levels in Hepatocellular Carcinoma Are Associated with Poorer Differentiation, Microvascular Invasion and Earlier Recurrence with Higher Serum Autotaxin Levels. (2016)
  • Author(s): Enooku K, Uranbileg B, Ikeda H, Kurano M, Sato M, Kudo H, Maki H, Koike K, Hasegawa K, Kokudo N, Yatomi Y.
  • Journal Title: PLoS One Volume: 11 Issue: 9 Pages: e0161825-e0161825
  • DOI: 10.1371/journal.pone.0161825
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sarcopenia, Intramuscular Fat Deposition, and Visceral Adiposity Independently Predict the Outcomes of Hepatocellular Carcinoma (2015)
  • Author(s): Fujiwara N, Nakagawa H, Kudo Y, Tateishi R, Taguri M, Watadani T, Nakagomi R, Kondo M, Nakatsuka T, Minami T, Sato M, Uchino K, Enooku K, Kondo Y, Asaoka Y, Tanaka Y, Ohtomo K, Shiina S, Koike K
  • Journal Title: J Hepatol Volume: 62 Issue: 1 Pages: 131-140
  • DOI: 10.1016/j.jhep.2015.02.031
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Decreased miR122 in hepatocellular carcinoma leads to chemoresistance with increased arginine (2015)
  • Author(s): Kishikawa T, Otsuka M, Tan PS, Ohno M, Sun X, Yoshikawa T, Shibata C, Takata A, Kojima K, Takehana K, Ohishi M, Ota S, Noyama T, Kondo Y, Sato M, Soga T, Hoshida Y, Koike K
  • Journal Title: Oncotarget Volume: 6 Pages: 8339-8352
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression (2015)
  • Author(s): Yoshikawa, T. Wu, J. Otsuka, M. Kishikawa, T. Ohno, M. Shibata, C. Takata, A. Han, F. Kang, Y. J. Chen, C. A. Shyu, A. B. Han, J. Koike, K
  • Journal Title: Nucleic Acids Res Volume: 43(15) Issue: 15 Pages: 7577-89
  • DOI: 10.1093/nar/gkv728
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] DNA methylation at hepatitis B viral integrants is associated with methylation at flanking human genomic sequences. (2015)
  • Author(s): Watanabe Y, Yamamoto H, Oikawa R, Toyota M, Yamamoto M, Kokudo N, Tanaka S, Arii S, Yotsuyanagi H, Koike K, Itoh F.
  • Journal Title: Genome Research Volume: 25(3) Issue: 3 Pages: 328-337
  • DOI: 10.1101/gr.175240.114
  • Peer Reviewed / Open Access
• [Presentation] NASH・肥満関連肝癌における特異的代謝異常に着目した発癌促進機構解明 (2017)
  • Author(s): 藤原直人、中川勇人、小池和彦
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] HBV mRNAと宿主microRNA let-7の相互作用 (2016)
  • Author(s): 小池和彦
  • Organizer: 犬山シンポジウム
  • Place of Presentation: 名鉄犬山ホテル
  • Year and Date: 2016-08-04
• [Presentation] 糖尿病・代謝と肝臓 (2016)
  • Author(s): 小池和彦
  • Organizer: 第29回肝臓フォーラム（東部）
  • Place of Presentation: 経団連会館
  • Year and Date: 2016-07-09
  • Invited
• [Presentation] 肝炎 (2016)
  • Author(s): 小池和彦
  • Organizer: 日本医学会公開フォーラム
  • Place of Presentation: 日本医師会館
  • Year and Date: 2016-06-18
  • Invited
• [Presentation] Impact of demographic changes on Internal Medicine (2016)
  • Author(s): Kazuhiko Koike
  • Organizer: 122th DGIM（ドイツ内科学会）
  • Place of Presentation: Mannheim Congress Center Rosengarten
  • Year and Date: 2016-04-11
  • Int'l Joint Research / Invited
• [Presentation] Body composition and prognosis of hepatocellular carcinoma (2016)
  • Author(s): Koike K
  • Organizer: 35thUS-Japan Cooperative Medical Sciences Program (USJCMSP) Meeting
  • Place of Presentation: North Bethesda, MD, USA
  • Year and Date: 2016-01-13
  • Int'l Joint Research / Invited
• [Presentation] MicroRNA and HBV pathogenesis (2015)
  • Author(s): Koike K
  • Organizer: 3rd Italy-Japan Liver Work Shop
  • Place of Presentation: Napoli University, Italy
  • Year and Date: 2015-10-26
  • Int'l Joint Research / Invited
• [Presentation] 50 years of hepatology in Japan: Past, Present and Future (2015)
  • Author(s): Koike K
  • Organizer: 20th Korean Association of the Study of the Liver
  • Place of Presentation: Busan, Korea
  • Year and Date: 2015-09-11
  • Int'l Joint Research / Invited
• [Presentation] 肝疾患と体質：我が国の肝臓病の現状 (2015)
  • Author(s): 小池和彦
  • Organizer: 第65回日本体質医学会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2015-07-04
  • Invited
• [Presentation] MicroRNAと肝臓 (2015)
  • Author(s): 小池和彦
  • Organizer: 肝細胞研究会
  • Place of Presentation: 米子コンベンションセンター（鳥取県・米子市）
  • Year and Date: 2015-06-05
  • Invited