Basic research on developing new anti-HBV therapeutic strategy for cccDNA elimination by DOCK11 knockdown in HBV infected hepatocytes

• Project/Area Number: 18K07966
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kanazawa University
• Principal Investigator: LI YING-YI 金沢大学, 医学系, 博士研究員 (70401940)
• Co-Investigator(Kenkyū-buntansha): 本多 政夫 金沢大学, 保健学系, 教授 (00272980)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: HBV / cccDNA / DOCK11 / Retrograde trafficking / Golgi / AGAP2 / ARF1 / antivirus therapy / Hepatitis B virus / Dock11 / infection / cccDNA stability / retrograde trafficking / assembly of HBV DNA

Outline of Final Research Achievements

Hepatitis B virus (HBV) infection is difficult to cure owing to the persistence of cccDNA. Here, we identified DOCK11, a guanine nucleotide exchange factor (GEF), as a candidate druggable target for HBV. Interestingly, DOCK11 functionally associated with retrograde trafficking proteins in trans-Golgi network (TGN), AGAP2 and ARF1 together with HBV capsid, to open an alternative retrograde trafficking route of HBV capsid from early endosomes (EEs) to the TGN and then to the endoplasmic reticulum (ER), thereby avoiding lysosomal degradation. cccDNA levels were strongly suppressed by shDOCK11. Surprisingly, combination of ETV plus shDOCK11 further reduced HBVDNA and cccDNA levels. Clinically, DOCK11 levels in the liver of patients with chronic hepatitis B were significantly reduced by entecavir treatment, and this reduction correlated with HBs antigen levels. Thus, DOCK11 could be a potential therapeutic target to prevent persistent HBV infection.

Academic Significance and Societal Importance of the Research Achievements

エンテカビル（ETV）によってウイルス複製を継続的に抑制しても，感染肝細胞核内に容易に排除されることのない HBV cccDNAが残存して，再活性化と発癌を引起す可能性は高い。本研究では，cccDNAの維持を制御する一つの機構を初めて解明し，B型肝炎の治療に新しい治療法を提案した。

Research Products

• [Journal Article] BMP9-ID1 Signaling Activates HIF-1α and VEGFA Expression to Promote Tumor Angiogenesis in Hepatocellular Carcinoma (2022)
  • Author(s): Chen Han、Nio Kouki、Tang Hong、Yamashita Taro、Okada Hikari、Li Yingyi、Doan Phuong Thi Bich、Li Ru、Lv Junyan、Sakai Yoshio、Yamashita Tatsuya、Mizukoshi Eishiro、Honda Masao、Kaneko Shuichi
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 3 Pages: 1475-1475
  • DOI: 10.3390/ijms23031475
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma (2021)
  • Author(s): Chen Han、Nio Kouki、Yamashita Taro、Okada Hikari、Li Ru、Suda Tsuyoshi、Li Yingyi、Doan Phuong Thi Bich、Seki Akihiro et.al
  • Journal Title: Molecular Oncology Volume: not available Issue: 8 Pages: 2203-2218
  • DOI: 10.1002/1878-0261.12963
  • Peer Reviewed / Open Access
• [Presentation] DOCK11 might be a candidate druggable target for HBV cure (2021)
  • Author(s): Ying-Yi LI, Masao Honda, Shuichi Kaneko.
  • Organizer: JDDW 2021
• [Presentation] A liver-derived secretory protein, LECT2, restores the impaired plasmacytoid dendritic cells function by HBV and protects hepatocytes against HBV infection (2018)
  • Author(s): Takayoshi shirasaki, Masao Honda, Tetsuro Shimakami, Kazunori Kawaguchi, Ying-Yi LI, Kouki Nio, Taro Yamashita, Shuichi Kaneko
  • Organizer: 2018 international HBV meeting
  • Int'l Joint Research
• [Presentation] mTORC2-Akt phosphorylation is associsted with Notch signaling activation by nucleotide analogues but not nucleoside analogues for chronic HBV infection (2018)
  • Author(s): Kazunori Kawaguchi, Zijing Wang, Masao Honda, takayoshi shirasaki, Hikari Okada, Ying-Yi Li, Kazuhisa Murai, Kouki Nio, Tetsuro Shimakami, Taro Yamashita, Shinichi Hashimoto, Kazuyuki kuroki, Seishi Murakami, Shuichi Kaneko
  • Organizer: 2018 international HBV meeting
  • Int'l Joint Research