Development of anticancer therapy targeting ADAM9 and NK cells in HCC

• Project/Area Number: 19K16723
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Showa University
• Principal Investigator: Jun Arai 昭和大学, 医学部, 講師 (30766176)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: MICA / NK細胞 / 肝細胞癌 / 癌免疫 / ロイコトリエン拮抗薬 / レチノイド / ADAM9 / レゴラフェニブ / 癌免疫療法

Outline of Research at the Start

GWASにより肝癌感受性遺伝子として同定された抗腫瘍免疫リガンドであるMHC class I polypeptide-related sequence A (MICA)の腫瘍細胞膜上の増加が、NK細胞による細胞傷害活性の増強に寄与する癌免疫療法として期待できる。本研究では、これまでの結果をもとに新たにin vitro ADAM9 assay system を樹立し、FDA承認薬ライブラリーを用いて薬剤探索を行い、ADAM9の酵素活性を抑制できる薬剤を発見する。抽出された薬剤の類縁体についても追加実験を行い、細胞傷害活性が低くMICA切断により強く関与している物質を同定する。

Outline of Final Research Achievements

Background/Aim:The association between MICA and HCC development was identified in our previous genome-wide association study. Decreasing soluble MICA (sMICA) through MICA sheddases suppression facilitates natural killer (NK) cell-mediated cytotoxicity. The expression of ADAM9 in HCC has been correlated with poor prognosis, and our recent study showed that its suppression contributes to cancer elimination by decreasing sMICA. Materials and Methods: Human HCC cell line PLC/PRF/5 and HepG2 cells were used. sMICA levels were measured by ELISA. Expression of RXRs and RARs was knocked down by siRNA. Results: In our screening of FDA-approved drugs in vitro, two leukotriene receptor antagonists (LTRAs), and retinoids were found to be efficient ADAM9 inhibitors. Treatment with LTRAs and retinoids reduced MICA shedding in human HCC cells.
Conclusion: LTRAs and retinoids can be potential novel agents for HCC treatment.

Academic Significance and Societal Importance of the Research Achievements

Natural killer細胞は腫瘍免疫の中心を担い、肝臓組織の約18％を占める。そのため正常な肝臓では癌細胞が発生しても、NK細胞により癌細胞が除去されやすい環境にある。我々はゲノムワイド関連解析によりC型肝炎の肝発癌に寄与する感受性遺伝子として抗NK細胞のリガンドであるMHC class I polypeptide-related sequence A（MICA）を同定した。今回新たにLTRAsとレチノイドがMICA切断抑止に寄与することを示した。
今後の肝臓病治療の目標として、肝癌予防法の発癌抑止法を検討すべき時代にさしかかっており、本課題は社会的にニーズの高い領域である。

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
• [Journal Article] Decreased expression of interferon‐stimulated genes in B cells of patients with chronic hepatitis C during interferon‐free therapy potentially suggests the eradication of hepatitis C virus in the B cells: A cohort study (2020)
  • Author(s): Arai Jun、Ito Takayoshi、Shimozuma Yuu、Uchikoshi Manabu、Nakajima Yoko、Sakaki Masashi、Uozumi Shojiro、Kajiwara Atsushi、Sugiura Ikuya、Otoyama Yumi、Nozawa Hisako、Kurihara Toshikazu、Eguchi Junichi、Nomura Norihiro、Sakuma Dai、Sato Masashi、Deguchi Yoshio、Yoshida Hitoshi
  • Journal Title: Health Science Reports Volume: 3 Issue: 3 Pages: 1-10
  • DOI: 10.1002/hsr2.176
  • Peer Reviewed / Open Access
• [Journal Article] Laparoscopic Treatment of a Hepatoduodenal Ligament Schwannoma With Infrared Indocyanine Green Fluorescence (2020)
  • Author(s): Tomioka K, Aoki T, Koizumi T, Elewa A, Kusano T, Matsuda K, Nogaki K, Tashiro Y, Wada Y, Hakozaki T, Shibata H, Hirai T, Yamazaki T, Saito K, Enami Y, Sugiura I, Nakajima Y, Arai J, Kajiwara A, Uozumi S, Shimozuma YU, Uchikoshi M, Sakaki M, Yoshida H, Miura S, Murakami M
  • Journal Title: In Vivo Volume: 34 Issue: 4 Pages: 2037-2041
  • DOI: 10.21873/invivo.12004
  • Peer Reviewed / Open Access
• [Journal Article] Three cases of histologically proven hepatic epithelioid hemangioendothelioma evaluated using a second-generation microbubble contrast medium in ultrasonography: case reports (2019)
  • Author(s): Jun Arai, Yuu Shimozuma, Yumi Otoyama, Ikuya Sugiura, Yoko Nakajima, et al
  • Journal Title: BMC Gastroenterology Volume: 19 Issue: 1 Pages: 187-194
  • DOI: 10.1186/s12876-019-1113-y
  • Peer Reviewed / Open Access
• [Presentation] 肝発癌感受性分子MICAの切断阻害を目的としたADAM9酵素活性抑制薬の探索 (2020)
  • Author(s): 音山裕美,荒井潤,吉田仁
  • Organizer: 第43回日本肝臓学会東部会
• [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: 第56回日本肝臓学会総会
• [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