Elucidation of molecular mechanism underlying NASH-HCC development by oncometabolite in chronic inflammation.

• Project/Area Number: 19K16749
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kumamoto University
• Principal Investigator: Arima Kota 熊本大学, 病院, 非常勤診療医師 (10792616)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肝癌 / 非アルコール性脂肪性肝炎 / プロスタグランジン / NASH / 肝細胞癌 / 15-PGDH / 代謝物

Outline of Research at the Start

近年、肥満や生活習慣病を背景とした非アルコール性脂肪性肝炎（NASH）由来の肝癌が増加している。肥満関連肝発癌メカニズムとしてPGE2シグナルは最も重要な炎症性シグナルであり、特にPGE2の分解酵素である15-PGDHの生体内での重要性が認識され始めている。本研究の目的は、15-PGDH発現がNASH肝癌の発癌・進展に与える影響について臨床サンプル・NASH肝癌マウスモデルを用いて検証し、基礎・臨床の双方より意義を明らかにすることである。マウスおよびヒト肝癌組織を用いた網羅的代謝物解析を行うことで、NASH肝癌の早期発見や新規治療戦略となり得る代謝物の同定が可能となる。

Outline of Final Research Achievements

Hepatocellular carcinoma (HCC) has been mostly occurred in the liver cirrhosis derived from hepatitis virus infection, however, HCC which is occurred in the liver derived from non-alcoholic steatohepatitis (NASH) has been increased recently. In the current study, we found that accumulation of PGE2 signal induced NASH-HCC development in NASH-HCC mice model and PGE2 signal might induce NASH-HCC development through immune cell exhaustion. Further analysis using comprehensive approach could inform research effort of developing NASH-HCC prevention strategies through anti-inflammatory modifications.

Academic Significance and Societal Importance of the Research Achievements

これまで肝癌はウイルス性肝炎を介したものが主流であったが、近年は肥満や生活習慣病を背景とした非アルコール性脂肪性肝炎（NASH）を背景としたNASH肝癌が世界中で増加している。従来の肝癌とは全く異なるメカニズムで生じており、発がん予防および治療のため詳細なメカニズム解明が必要であるが、当研究は大腸がんなどに深く関与しているプロスタグランジンシグナルがNASH肝癌の発がん・進展に深く関連している可能性を明らかにした。さらなる解析により、NASH肝癌浸潤の新たな分子メカニズムの解明に繋がる。

Research Products

• [Journal Article] Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination (2021)
  • Author(s): Yasuda T, Koiwa M, Yonemura A, Miyake K, Kariya R, Kubota S, Yokomizo-Nakano T, Yasuda-Yoshihara N, Uchihara T, Itoyama R, Bu L, Fu L, Arima K, Izumi D, Iwagami S, Eto K, Iwatsuki M, Baba Y, Yoshida N, Ohguchi H, Okada S, Matsusaki K, Sashida G, Takahashi A, Tan P, Baba H, Ishimoto T.
  • Journal Title: Cell Reports Volume: 34 Issue: 8 Pages: 108779-108779
  • DOI: 10.1016/j.celrep.2021.108779
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical role of serum programmed death ligand 1 in patients with hepatocellular carcinoma: Where does it come from? (2020)
  • Author(s): Elmezayen Hatem A.、Okabe Hirohisa、Baba Yoshifumi、Yusa Toshihiko、Itoyama Rumi、Nakao Yosuke、Yamao Takanobu、Umzaki Naoki、Tsukamoto Masayo、Kitano Yuki、Miyata Tatsunori、Arima Kota、Hayashi Hiromitsu、Imai Katsunori、Chikamoto Akira、Yamashita Yo-ichi、Baba Hideo
  • Journal Title: Surgery Today Volume: 50 Issue: 6 Pages: 569-576
  • DOI: 10.1007/s00595-019-01920-8
  • Peer Reviewed
• [Journal Article] Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing β1 Integrin, Enhancing Drug Resistance (2020)
  • Author(s): Uchihara T, Miyake K, Yonemura A, Komohara Y, Itoyama R, Koiwa M, Yasuda T, Arima K, Harada K, Eto K, Hayashi H, Iwatsuki M, Iwagami S, Baba Y, Yoshida N, Yashiro M, Masuda M, Ajani Jaffer A, Tan Patrick, Baba H, Ishimoto T
  • Journal Title: Cancer Research Volume: 80 Issue: 16 Pages: 3222-3235
  • DOI: 10.1158/0008-5472.can-19-3803
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of Repeated Hepatectomy on Liver Regeneration in Hepatocellular Carcinoma: A Propensity Score-based Analysis. (2019)
  • Author(s): Arima K, Nitta H, Beppu T, Nakagawa S, Okabe H, Imai K, Chikamoto A, Yamashita YI, Yamashita Y, Baba H.
  • Journal Title: Anticancer Research Volume: 39 Pages: 965-970
  • Peer Reviewed
• [Presentation] Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas. (2019)
  • Author(s): Ishimoto T, Arima K, Uchihara T, Miyake K, Yonemura A, Yasuda T, Itoyama R, Iwatsuki M, Baba Y, Yoshida N, Baba H.
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research