Development of the innovative chemopreventive strategy for metabolic syndrome-related liver carcinogenesis by targeting multiple organ network

• Project/Area Number: 16K09352
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Gifu University
• Principal Investigator: Shimizu Masahito 岐阜大学, 大学院医学系研究科, 教授 (90402198)
• Co-Investigator(Kenkyū-buntansha): 白木 亮 岐阜大学, 大学院医学系研究科, 准教授 (60402195) ; 白上 洋平 岐阜大学, 大学院医学系研究科, 助教 (50632816)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: メタボ肝癌 / 臓器間ネットワーク / 生活習慣病 / 非アルコール性脂肪肝炎 / 核内受容体RXR / レチノイド

Outline of Final Research Achievements

The results of the present study showed that both activation of retinoid signaling and inhibition of sodium glucose transporter-2 were effective ways to suppress non-alcoholic steatohepatitis-, obesity-, and lifestyle disease-related liver tumorigenesis. This study also revealed that a higher dose of loop diuretic use was associated with more rapid skeletal muscle depletion and poor survival in patients with liver cirrhosis. In addition, increased visceral fat volume and insulin resistance raised the risk for recurrence of hepatocellular carcinoma after curative treatment. These findings may suggest that the control of the organ network composed of liver, skeletal muscle, and visceral fat is effective way to suppress metabolic syndrome-related liver carcinogenesis. Moreover, abnormality of the network, especially insulin resistance, is significantly associated with poor prognosis of patients with liver cirrhosis and hepatocellular carcinoma.

Academic Significance and Societal Importance of the Research Achievements

肝臓、骨格筋、内臓脂肪等はそれぞれが独立した臓器ではなく、生体内においてネットワークを形成している。本研究は、標的臓器（肝臓）のみではなく、肥満・生活習慣病によって惹起された臓器間ネットワークの異常・恒常性の破綻にアプローチして肝発癌予防を実践するという、斬新かつ独創的なコンセプトに基づいた研究である。肥満や糖尿病、生活習慣病が大きな社会問題である現在、これらの病態や非アルコール性脂肪肝炎を背景とする肝細胞癌は増加している。肝臓をエネルギー代謝臓器間ネットワークの中心臓器として行った本研究の成果は、社会・国民が大きな期待を寄せるメタボ肝癌の有益な診断・治療法の開発に繋がる。

Research Products

• [Journal Article] Effect of loop diuretics on skeletal muscle depletion in patients with liver cirrhosis. (2019)
  • Author(s): Hanai T, Shiraki M, Miwa T, Watanabe S, Imai K, Suetsugu A, Takai K, Moriwaki H, Shimizu M.
  • Journal Title: Hepatol Res. Volume: 49 Issue: 1 Pages: 82-95
  • DOI: 10.1111/hepr.13244
  • NAID: 40021909580
  • Peer Reviewed / Open Access
• [Journal Article] A nationwide survey on non-B, non-C hepatocellular carcinoma in Japan: 2011-2015 update. (2019)
  • Author(s): Tateishi R, Uchino K, Fujiwara N, Takehara T, Okanoue T, Seike M, Yoshiji H, Yatsuhashi H, Shimizu M, Torimura T, Moriyama M, Sakaida I, Okada H, Chiba T, Chuma M, Nakao K, Isomoto H, Sasaki Y, Kaneko S, Masaki T, Chayama K, Koike K.
  • Journal Title: J Gastroenterol. Volume: 54 Issue: 4 Pages: 367-376
  • DOI: 10.1007/s00535-018-1532-5
  • Peer Reviewed / Open Access
• [Journal Article] Homeostatic Model Assessment of Insulin Resistance for Predicting the Recurrence of Hepatocellular Carcinoma after Curative Treatment. (2019)
  • Author(s): Imai K, Takai K, Hanai T, Suetsugu A, Shiraki M, Shimizu M.
  • Journal Title: Int J Mol Sci. Volume: 20 Issue: 3 Pages: 605-605
  • DOI: 10.3390/ijms20030605
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic significance of minimal hepatic encephalopathy in patients with liver cirrhosis in Japan: A propensity score-matching analysis. (2019)
  • Author(s): Hanai T, Shiraki M, Watanabe S, Imai K, Suetsugu A, Takai K, Moriwaki H, Shimizu M.
  • Journal Title: J Gastroenterol Hepatol. Volume: - Issue: 10 Pages: 1809-1816
  • DOI: 10.1111/jgh.14635
  • Peer Reviewed / Open Access
• [Journal Article] Increased visceral fat volume raises the risk for recurrence of hepatocellular carcinoma after curative treatment. (2018)
  • Author(s): Imai K, Takai K, Maeda T, Watanabe S, Hanai T, Suetsugu A, Shiraki M, Shimizu M.
  • Journal Title: Oncotarget Volume: 9 Issue: 18 Pages: 14058-14067
  • DOI: 10.18632/oncotarget.24500
  • Peer Reviewed / Open Access
• [Journal Article] Prevention of hepatocellular carcinoma by targeting MYCN-positive liver cancer stem cells with acyclic retinoid (2018)
  • Author(s): Qin XY, Suzuki H, Honda M, Okada H, Kaneko S, Inoue I, Ebisui E, Hashimoto K, Carninci P, Kanki K, Tatsukawa H, Ishibashi N, Masaki T, Matsuura T, Kagechika H, Toriguchi K, Hatano E, Shirakami Y, Shiota G, Shimizu M, Moriwaki H, Kojima S
  • Journal Title: Proc Natl Acad Sci U S A Volume: 115 Issue: 19 Pages: 4969-4974
  • DOI: 10.1073/pnas.1802279115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sarcopenia impairs prognosis of patients with hepatocellular carcinoma: The role of liver functional reserve and tumor-related factors in loss of skeletal muscle volume. (2017)
  • Author(s): Imai K, Takai K, Watanabe S, Hanai T, Suetsugu A, Shiraki M, Shimizu M.
  • Journal Title: Nutrients Volume: 9 Issue: 10 Pages: 1054-1054
  • DOI: 10.3390/nu9101054
  • Peer Reviewed / Open Access
• [Journal Article] Sarcopenia predicts minimal hepatic encephalopathy in patients with liver cirrhosis. (2017)
  • Author(s): Hanai T, Shiraki M, Watanabe S, Kochi T, Imai K, Suetsugu A, Takai K, Moriwaki H, Shimizu M.
  • Journal Title: Hepatol Res Volume: 47 Issue: 13 Pages: 1359-1367
  • DOI: 10.1111/hepr.12873
  • Peer Reviewed
• [Journal Article] Non-alcoholic steatohepatitis-related liver tumorigenesis is suppressed in mice lacking hepatic retinoid storage (2017)
  • Author(s): Ideta, T. Shirakami, Y. Ohnishi, M. Maruta, A. Obara, K. Miyazaki, T. Kochi, T. Sakai, H. Tomita, H. Tanaka, T. Blaner, W. S. Shimizu, M.
  • Journal Title: Oncotarget Volume: 8 Issue: 41 Pages: 70695-70706
  • DOI: 10.18632/oncotarget.19978
  • Peer Reviewed / Open Access
• [Journal Article] Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice. (2017)
  • Author(s): Obara K, Shirakami Y, Maruta A, Ideta T, Miyazaki T, Kochi T, Sakai H, Tanaka T, Seishima M, Shimizu M.
  • Journal Title: Oncotarget Volume: 8 Issue: 35 Pages: 58353-58363
  • DOI: 10.18632/oncotarget.16874
  • Peer Reviewed / Open Access
• [Journal Article] Alpha-glucosidase inhibitor use is associated with decreased colorectal neoplasia risk in patients with type 2 diabetes mellitus receiving colonoscopy: a retrospective study. (2017)
  • Author(s): Horibe Y, Adachi S, Ohno T, Goto N, Okuno M, Iwama M, Yamauchi O, Kojima T, Saito K, Ibuka T, Yasuda I, Araki H, Moriwaki H, Shimizu M.
  • Journal Title: Oncotarget Volume: 8 Issue: 58 Pages: 97862-97870
  • DOI: 10.18632/oncotarget.18416
  • Peer Reviewed / Open Access
• [Journal Article] Preventative Effects of Pentoxifylline on the Development of Colonic Premalignant Lesions in Obese and Diabetic Mice (2017)
  • Author(s): Fukuta K, Shirakami Y, Maruta A, Obara K, Iritani S, Nakamura N, Kochi T, Kubota M, Sakai H, Tanaka T, Shimizu M
  • Journal Title: Int J Mol Sci Volume: 18(2) Issue: 2 Pages: 413-413
  • DOI: 10.3390/ijms18020413
  • Peer Reviewed / Open Access
• [Journal Article] Imaging the role of multinucleate pancreatic cancer cells and cancer-associated fibroblasts in peritoneal metastasis in mouse models. (2017)
  • Author(s): Hasegawa K, Suetsugu A, Nakamura M, Matsumoto T, Aoki H, Kunisada T, Shimizu M, Saji S, Moriwaki H, Hoffman RM.
  • Journal Title: Anticancer Res Volume: 37 Pages: 3435-3440
  • Peer Reviewed
• [Journal Article] Genetic recombination between stromal and cancer cells results in highly malignant cells identified by color-coded imaging in a mouse lymphoma model. (2017)
  • Author(s): Nakamura M, Suetsugu A, Hasegawa K, Matsumoto T, Aoki H, Kunisada T, Shimizu M, Saji S, Moriwaki H, Hoffman RM.
  • Journal Title: J Cell Biochem Volume: - Issue: 12 Pages: 4216-4221
  • DOI: 10.1002/jcb.26068
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Choline-deficient-diet-induced fatty liver is a metastasis-resistant microenvironment. (2017)
  • Author(s): Nakamura M, Suetsugu A, Hasegawa K, Matsumoto T, Aoki H, Kunisada T, Shimizu M, Saji S, Moriwaki H, Hoffman RM.
  • Journal Title: Anticancer Res Volume: 37 Pages: 3429-3434
  • Peer Reviewed
• [Journal Article] Preventive effects of astaxanthin on diethylnitrosamine-induced liver tumorigenesis in C57/BL/KsJ-db/db obese mice. (2016)
  • Author(s): Ohno T, Shimizu M, Shirakami Y, Miyazaki T, Ideta T, Kochi T, Kubota M, Sakai H, Tanaka T, Moriwaki H.
  • Journal Title: Hepatol Res. Volume: 46(3) Issue: 3 Pages: 201-209
  • DOI: 10.1111/hepr.12550
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Development of a novel scoring system for predicting the risk of colorectal neoplasia: A retrospective study. (2016)
  • Author(s): Ohno T, Adachi S, Okuno M, Horibe Y, Goto N, Iwama M, Yamauchi O, Kojima T, Saito K, Ibuka T, Yasuda I, Araki H, Moriwaki H, Shimizu M.
  • Journal Title: PLoS One Volume: 11 Issue: 6 Pages: e0157269-e0157269
  • DOI: 10.1371/journal.pone.0157269
  • Peer Reviewed
• [Journal Article] The Role of Indoleamine 2,3-Dioxygenase in Diethylnitrosamine-Induced Liver Carcinogenesis (2016)
  • Author(s): Shibata Y, Hara T, Nagano J, Nakamura N, Ohno T, Ninomiya S, Ito H, Tanaka T, Saito K, Seishima M, Shimizu M, Moriwaki H, Tsurumi H
  • Journal Title: Leukemia Lymphoma Volume: 11 Issue: 1 Pages: 4-11
  • DOI: 10.1371/journal.pone.0146279
  • Peer Reviewed
• [Journal Article] The deficiency of indoleamine 2,3-dioxygenase aggravates the CCl4-induced liver fibrosis in mice. (2016)
  • Author(s): Ogiso H, Ito H, Ando T, Arioka Y, Kanbe A, Ando K, Ishikawa T, Saito K, Hara A, Moriwaki H, Shimizu M, Seishima M.
  • Journal Title: PLoS One Volume: 11 Issue: 9 Pages: e0162183-e0162183
  • DOI: 10.1371/journal.pone.0162183
  • NAID: 120005853278
  • Peer Reviewed
• [Journal Article] Sodium alginate prevents progression of non-alcoholic steatohepatitis and liver carcinogenesis in obese and diabetic mice. (2016)
  • Author(s): Miyazaki T, Shirakami Y, Kubota M, Ideta T, Kochi T, Sakai H, Tanaka T, Moriwaki H, Shimizu M.
  • Journal Title: Oncotarget Volume: - Issue: 9 Pages: 10448-10458
  • DOI: 10.18632/oncotarget.7249
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cimetidine and Clobenpropit Attenuate Inflammation-Associated Colorectal Carcinogenesis in Male ICR Mice (2016)
  • Author(s): Tanaka T, Kochi T, Shirakami Y, Mori T, Kurata A, Watanabe N, Moriwaki H, Shimizu M
  • Journal Title: Cancers Volume: 8 Issue: 2 Pages: 25-25
  • DOI: 10.3390/cancers8020025
  • Peer Reviewed
• [Journal Article] Different susceptibilities between Apoe- and Ldlr-deficient mice to inflammation-associated colorectal carcinogenesis. (2016)
  • Author(s): Tanaka T, Oyama T, Sugie S, Shimizu M.
  • Journal Title: Int J Mol Sci Volume: 17
  • Peer Reviewed
• [Journal Article] Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model. (2016)
  • Author(s): Qin, X-Y., Tatsukawa, H., hitomi, K., Shirakami, Y., Ishibashi, N., Shimizu, M., Moriwaki, H., and *Kojima, S.
  • Journal Title: Cancer Prevention Res. Volume: 9(3) Issue: 3 Pages: 205-214
  • DOI: 10.1158/1940-6207.capr-15-0326
  • Peer Reviewed
• [Journal Article] Chemoprevention of obesity-related liver carcinogenesis by using pharmaceutical and nutraceutical agents. (2016)
  • Author(s): Sakai H, Shirakami Y, Shimizu M.
  • Journal Title: World J Gastroenterol Volume: 22(1) Issue: 1 Pages: 394-406
  • DOI: 10.3748/wjg.v22.i1.394
  • Peer Reviewed / Open Access
• [Journal Article] Pentoxifylline prevents non-alcoholic steatohepatitis-related liver pre-neoplasms by inhibiting hepatic inflammation and lipogenesis. (2015)
  • Author(s): Shirakami Y, Shimizu M, Kubota M, Ohno T, Kochi T, Nakamura N, Sumi T, Tanaka T, Moriwaki H, Seishima M.
  • Journal Title: Eur J Cancer Prev Volume: 25 Issue: 3 Pages: 206-215
  • DOI: 10.1097/cej.0000000000000172
  • Peer Reviewed
• [Journal Article] Rapid skeletal muscle wasting predicts worse survival in patients with liver cirrhosis. (2015)
  • Author(s): Hanai T, Shiraki M, Ohnishi S, Miyazaki T, Ideta T, Kochi T, Imai K, Suetsugu A, Takai K, Moriwaki H, Shimizu M.
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 8 Pages: 743-751
  • DOI: 10.1111/hepr.12616
  • Peer Reviewed
• [Presentation] シンポジウム3「骨格筋と慢性肝疾患」 慢性肝疾患とサルコぺニアー予後改善をめざした栄養療法ー (2018)
  • Author(s): 清水雅仁
  • Organizer: 第8回肥満と消化器疾患研究会
• [Presentation] 白木 亮 岩佐元雄 小池和彦 (2018)
  • Author(s): パネルディスカッション6「肝硬変のQOL改善を目指した総合的治療戦略」 日本の多施設共同研究からみた慢性肝疾患における筋痙攣の実態
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] シンポジウム4「肝疾患におけるサルコペニアの診断と治療」 肝硬変患者におけるループ利尿剤と骨格筋減少に関する後ろ向き観察研究 (2018)
  • Author(s): 華井竜徳 白木 亮 清水雅仁
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] シンポジウム3「門亢症の包括的マネジメント」 慢性肝疾患患者における筋力低下と予後の検討 (2018)
  • Author(s): 白木 亮 華井竜徳 清水雅仁
  • Organizer: 第25回日本門脈圧亢進症学会
• [Presentation] ミニシンポジウム「核内受容体とそのリガンドの化学・生物学・医学」 核内受容体とそのリガンドの医学 (2018)
  • Author(s): 白上洋平 境 浩康 清水雅仁
  • Organizer: 日本レチノイド研究会第29回学術集会
• [Presentation] パネルディスカッション「生活習慣病・メタボリックシンドロームからの消化器疾患」 酸化ストレスの制御による肥満関連大腸発癌の抑制 (2017)
  • Author(s): 白上洋平 清水雅仁 清島 満
  • Organizer: 第103回日本消化器病学会総会
• [Presentation] ワークショップ11「肝硬変のトタルケア・マネージメント」 慢性肝疾患患者の筋力低下についての検討 (2017)
  • Author(s): 白木 亮 華井竜徳 清水雅仁
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] ワークショップ「消化器疾患と代謝異常の関わり」糖尿病治療薬を用いた肥満に関連する肝疾患の抑制 (2016)
  • Author(s): 白上洋平, 清水雅仁, 清島 満
  • Organizer: JDDW2016（第58回日本消化器病学会大会）
  • Place of Presentation: 神戸