Elucidation of the role of NKG2D ligands in HBV-related hepatocellular carcinoma

• Project/Area Number: 18K07996
• 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: Chiba University
• Principal Investigator: Ryosuke MUROYAMA 千葉大学, 大学院医学研究院, 助教 (50549459)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: B型肝炎ウイルス / 肝細胞癌 / 自然免疫システム / NKG2Dリガンド / B型肝癌

Outline of Final Research Achievements

Using RNA-seq data from in HBV-related hepatocellular carcinoma (HCC) tissue, we investigated differentially expressed genes, and found that MICA and MICB expression level is up-regulated. In DNA methylation analysis, the promoter region of genes was generally hypo-methylated in HCC tissue, and the abnormal DNA methylation in genes associated with immune response was suggested to be hepatocarcinogenesis. We constructed vectors expressing full-length MICA and ΔN-MICA (MICA with with a truncation at the N-terminus). After introducing them into hepatoma cell line, we measured the expression level of soluble full-length MICA and ΔN-MICA in supernatant of cell culture using ELISA, and found that the ΔN-MICA expression was almost undetected. This results was suggested that the dynamics in liver cells between them was completely different.

Academic Significance and Societal Importance of the Research Achievements

B型肝炎ウイルス（HBV）感染による肝発癌、すなわちB型肝癌に対する有効な治療法の開発は、肝臓病学において、克服すべき最重要課題の1つである。本研究により、B型肝癌組織において、NKG2Dリガンドに属するMICA, MICBの発現上昇が認められ、「NKG2Dリガンド-NK細胞」を含む自然免疫システムに属する遺伝子群の発現変動が起こっていることが明らかとなった。このことは、「NKG2Dリガンド-NK細胞」という自然免疫システムを強化することでB型肝癌を制御する、すなわちB型肝癌に対する新規の免疫療法の開発につながる重要な知見と考えられる。

Research Products

• [Journal Article] Leukotriene receptor antagonists enhance HCC treatment efficacy by inhibiting ADAMs and suppressing MICA shedding (2021)
  • Author(s): Arai J, Goto K, Otoyama Y, Nakajima Y, Sugiura I, Kajiwara A, Tojo M, Ichikawa Y, Uozumi S, Shimozuma Y, Uchikoshi M, Sakaki M, Nozawa H, Nakagawa R, Muroyama R, Kato N, Yoshida H.
  • Journal Title: Cancer Immunol Immunother Volume: 70 Issue: 1 Pages: 203-213
  • DOI: 10.1007/s00262-020-02660-2
  • Peer Reviewed / Open Access
• [Presentation] ADAM9酵素活性阻害によるMICA-NK axisを標的とした肝癌治療戦略 (2020)
  • Author(s): 荒井潤, 後藤覚,音山裕美, 杉浦育也, 中島陽子, 梶原敦, 市川雪, 魚住祥二郎, 下間祐, 打越学, 坂木理, 中川良, 室山良介, 加藤直也,吉田仁
  • Organizer: 第56回日本肝臓学会総会
• [Presentation] レチノイン酸による肝発癌感受性分子MICAの制御効果 (2020)
  • Author(s): 音山裕美, 荒井潤, 杉浦育也, 中島陽子, 梶原敦, 市川雪, 魚住祥二郎, 下間祐, 打越学, 坂木理, 後藤覚, 中川良, 室山良介, 加藤直也, 吉田仁
  • Organizer: 56回日本肝臓学会総会
• [Presentation] レゴラフェニブ治療が大腸癌に与えるNK細胞活性化シグナルへの影響 (2020)
  • Author(s): 荒井潤, 後藤覚, 音山裕美, 杉浦育也, 中島陽子, 梶原敦, 市川雪, 魚住祥二郎, 下間祐, 打越学, 坂木理, 中川良, 室山良介, 加藤直也, 吉田仁
  • Organizer: 第106回日本消化器病学会総会
• [Presentation] NGSデータを用いた網羅的ゲノム解析による肝癌関連遺伝子の探索 (2019)
  • Author(s): 室山良介、神﨑洋彰、加藤直也
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] Identification of modules and hub genes associated with HBV-HCC by gene co-expression analysis (2019)
  • Author(s): Ryosuke Muroyama, Hiroaki Kanzaki, Tetsuhiro Chiba, Masato Nakamura, Shingo Nakamoto, Hiroshi Shirasawa, Naoya Kato
  • Organizer: International HBV meeting
  • Int'l Joint Research
• [Presentation] NGSデータを用いたゲノム異常解析に基づく肝癌関連遺伝子の探索 (2018)
  • Author(s): 室山良介, 神崎洋彰, 加藤直也
  • Organizer: 第42回日本肝臓学会東部会
• [Presentation] 2.The exploration of cancer-related gene alterations using whole-genome sequencing data in HBV-related hepatoma cell line (2018)
  • Author(s): Ryosuke Muroyama, Hiroaki Kanzaki, Tetsuhiro Chiba, Ryo Nakagawa, Masato Nakamura, Shingo Nakamoto, Shin Yasui, Hiroshi Shirasawa, Naoya Kato
  • Organizer: International HBV Meeting
  • Int'l Joint Research