Search for new therapeutic targets for obesity-induced liver cancer focusing on mRNA degradation regulation

• Project/Area Number: 20K16309
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Osaka Metropolitan University (2022); Osaka City University (2020-2021)
• Principal Investigator: Yamagishi Ryota 大阪公立大学, 大学院医学研究科, 助教 (30793145)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肥満誘導性肝がん / SASP / 細胞老化 / GSDMD / mRNA安定性 / mRNA代謝制御 / mRNA代謝

Outline of Research at the Start

SASP因子遺伝子間でmRNAの配列的相同性を比較したところ、ほとんどのSASP 因子はmRNA上に3’末端非翻訳領域内にAU rich element (ARE)と呼ばれる共通配列を有していることが確認された。そこで、本研究ではAREを介したmRNA分解制御に着目し、SASP発現制御機構の解明を行う。初年度は、1) SASP mRNAの発現上昇がmRNAの安定化によること、2) 安定化を起こす鍵となる因子、を示すことでSASP発現制御の分子機構を明らかにする。次年度以降は、明らかにした制御機構が3) マウスモデル系及び4) ヒトで肝がんの進展に寄与することを検証する。

Outline of Final Research Achievements

In recent years, the number of patients with obesity-induced hepatocellular carcinoma (HCC) based on fatty liver has been increasing steadily, and the development of preventive and treatment methods is urgently needed. In this study, as a result of analyzing the SASP factors related to the development of obesity-induced liver cancer, we found that the cytokine IL-33 is a SASP factor that is particularly highly expressed in hepatic stellate cells (HSCs) in the obesity-induced liver tumor. Furthermore, as a mechanism for the extracellular release of SASP factors, the SASP factor IL-33 is released outside the HSCs through pores formed on the cell membrane by the pyroptosis-executing factor gasdermin D. The released IL-33 promoted HCC development through activating ST2-positive Treg cells. Our findings could lead to new insights for understanding obesity-induced HCC progression.

Academic Significance and Societal Importance of the Research Achievements

肝がんは、5年生存率が35.8％程度(がん腫別統計2021）と低い。そのため、肝がんの原因遺伝子を探るためのゲノム解析が、世界的に進められているが、発症に結び付く特定の原因遺伝子変異は見つかっていない。その中で、これまで肝がんの半数以上を占めてきたウイルス性肝がんは有効な抗ウイルス薬の開発により減少傾向となっている。一方で、脂肪肝を背景とする肥満誘導性肝がんは著しい増加傾向にあり、その予防法・治療法の開発は喫緊の課題となっている。そのため、肝がん微小環境に着目した本研究の成果は、肥満誘導性肝がんの治療法開発に繋がる有用な成果であると考えられる。

Research Products

• [Journal Article] Gasdermin D-mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma (2022)
  • Author(s): Yamagishi R, Kamachi F, Nakamura M, Yamazaki S, Kamiya T, Takasugi M, Cheng Y, Nonaka Y, Yukawa-Muto Y, Thuy LTT, Harada Y, Arai T, Loo TM, Yoshimoto S, Ando T, Nakajima M, Taguchi H, Ishikawa T, Akiba H, Miyake S, Kubo M, Iwakura Y, Fukuda S, Chen WY, Kawada N, Rudensky A, Nakae S, Hara E, Ohtani N
  • Journal Title: Science Immunology Volume: 7 Issue: 72 Pages: abl7209
  • DOI: 10.1126/sciimmunol.abl7209
  • URL: https://ocu-omu.repo.nii.ac.jp/records/2020472
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-heat-stressed Method to Isolate Hepatic Stellate Cells From Highly Steatotic Tumor-bearing Liver Using CD49a (2022)
  • Author(s): Yi Cheng, Ryota Yamagishi, Yoshiki Nonaka, Misako Sato-Matsubara, Norifumi Kawada, Naoko Ohtani
  • Journal Title: Cellular and molecular gastroenterology and hepatology Volume: 14 Issue: 4 Pages: 964-966.e9
  • DOI: 10.1016/j.jcmgh.2022.07.006
  • URL: https://ocu-omu.repo.nii.ac.jp/records/2019707
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] がん微小環境における細胞老化とSASPの役割：ガスダーミンDを介するSASP因子の放出が肥満関連肝がんを促進させる (2023)
  • Author(s): 山岸良多、蒲池史卓、神谷知憲、高杉征樹、程イ、野中允幾、河田則文、中江進、原英二、大谷直子
  • Organizer: 日本生理学会第100回記念大会
  • Invited
• [Presentation] IL-33によるNASH関連肝がん促進機構、山岸良多、武藤芳美、河田則文、大谷直子、第59回日本肝臓学会総会 (2022)
  • Author(s): 山岸良多、武藤芳美、河田則文、大谷直子
  • Organizer: 第59回日本肝臓学会総会
• [Presentation] IL-33 released from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma (2022)
  • Author(s): Ryota Yamagishi, Fumitaka Kamachi, Tomonori Kamiya, Yi Cheng, Yoshiki Nonaka, Norifumi Kawada, Susumu Nakae, Eiji Hara, Naoko Ohtani
  • Organizer: APASL Oncology 2022 Single Topic conference in Takamatsu
  • Int'l Joint Research
• [Presentation] IL-33 released from senescent hepatic stellate cell promotes obesity-associated hepatocellular carcinoma (2022)
  • Author(s): Ryota Yamagishi, Fumitaka Kamachi, Yi Cheng, Norifumi Kawada, Eiji Hara, Naoko Ohtani
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Regular exercise suppresses obesity associated liver cancer through activating Pgc-1α-Kynurenine degrading pathway (2022)
  • Author(s): Vu Thuong Huyen, Ryota Yamagishi, Naoko Ohtani
  • Organizer: APASL Oncology 2022 Single Topic conference in Takamatsu
  • Int'l Joint Research
• [Presentation] Regular exercise suppresses obesity associated liver cancer through activating Pgc-1α-Kynurenine degrading pathway (2022)
  • Author(s): Vu Thuong Huyen, Ryota Yamagishi, Naoko Ohtani
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] 肥満誘導性肝がん微小環境における腫瘍促進ネットワークの複合バイオインフォマティクス解析 (2022)
  • Author(s): 野中允幾、 山岸良多、 程イ、 大谷直子
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Combined Bioinformatics on the Tumor Promoting Inter-cellular Network in Obesity-associated Liver Tumor Microenvironment (2022)
  • Author(s): Yoshiki Nonaka, Ryota Yamagishi, Yi Cheng, Naoko Ohtani
  • Organizer: APASL Oncology 2022 Single Topic conference in Takamatsu
  • Int'l Joint Research
• [Presentation] 肥満誘導性肝がん微小環境における腫瘍促進ネットワークの複合解析 (2022)
  • Author(s): 野中允幾、 山岸良多、 程イ、 小玉尚宏、 大谷直子
  • Organizer: NGS EXPO 2022
• [Presentation] Gut-liver Axis-mediated Mechanism of NASH-associated Hepatocellular Carcinoma Progression (2021)
  • Author(s): Ryota Yamagishi, Fumitaka Kamachi, Tomonori Kamiya, Yoshiki Nonaka, Yoshimi Muto-Yukawa, Norifumi Kawada, Susumu Nakae, Eiji Hara, Naoko Ohtani
  • Organizer: APASL Single Topic Conference 2021 Osaka
  • Int'l Joint Research
• [Presentation] A Novel Isolation Method of Hepatic Stellate Cells from Tumor Tissue of Obesity-associated Hepatocellular Carcinoma (2021)
  • Author(s): Yi Cheng, Ryota Yamagishi, Yoshiki Nonaka, Huyen T. Vu, Yoshimi Yukawa-Muto, Misako Sato-Matsubara, Norifumi Kawada, Naoko Ohtani
  • Organizer: APASL Single Topic Conference 2021 Osaka
  • Int'l Joint Research
• [Presentation] 肥満関連肝癌腫瘍組織からの肝星細胞の分離法 (2021)
  • Author(s): 程 イ、大谷 直子、山岸 良多、蒲池 史卓
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] シングルセル解析を利用した肥満誘導性肝がん微小環境における肝星細胞の系譜・性質解明 (2021)
  • Author(s): 野中 允幾、山岸 良多、大谷 直子
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] Gut-liver axis-mediated mechanism of NASH-associated hepatocellular carcinoma progression (2021)
  • Author(s): Ryota Yamagishi, Fumitaka Kamachi, Tomonori Kamiya, Yoshiki Nonaka, Yoshimi Muto-Yukawa, Norifumi Kawada, Susumu Nakae, Eiji Hara, Naoko Ohtani
  • Organizer: 6th International Cell Senescence Association (ICSA) Conference
  • Int'l Joint Research
• [Presentation] enescence phenotype in freshly isolated hepatic stellate cells (HSCs) by non-heat-stressed method from obesity-associated steatotic hepatocellular carcinoma (2021)
  • Author(s): Yi Cheng, Ryota Yamagishi, Yoshiki Nonaka, Naoko Ohtani
  • Organizer: 6th International Cell Senescence Association (ICSA) Conference
  • Int'l Joint Research
• [Presentation] 肥満誘導性肝がん微小環境におけるSASP制御機構 (2020)
  • Author(s): 山岸 良多, 蒲池 史卓, 程 イ, 原 英二, 大谷 直子
  • Organizer: 日本癌学会総会
• [Presentation] がんと代謝(免疫代謝を含む) 腸内細菌代謝物と肥満関連肝がん (2020)
  • Author(s): 大谷 直子, 神谷 知憲, 蒲池 史卓, 山岸 良多
  • Organizer: 日本癌学会総会
• [Presentation] LATS2変異を有した悪性中皮腫におけるSMG6発現抑制による合成致死誘導機構の検討 (2020)
  • Author(s): 鈴木 浩也, 山岸 良多, 向井 智美, 田部 陽子, 三井田 孝, 関戸 好孝, 村上 優子
  • Organizer: 日本癌学会総会
• [Presentation] LATS2変異を有した悪性中皮腫に対する合成致死誘導機構の検討 (2020)
  • Author(s): 鈴木 浩也, 山岸 良多, 向井 智美, 田部 陽子, 三井田 孝, 村上 浩士, 関戸 好孝, 村上 優子[渡並]
  • Organizer: 日本薬学会年会
• [Patent(Industrial Property Rights)] 固形がんの予防及び/又は治療薬 (2022)
  • Inventor(s): 大谷直子、山岸良多
  • Industrial Property Rights Holder: 大谷直子、山岸良多
  • Industrial Property Rights Type: 特許
  • Filing Date: 2022