Elucidation of new target molecules preventing obesity-related liver carcinogenesis

• Project/Area Number: 25460988
• 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, 医学(系)研究科(研究院), 教授 (90402198)
• Co-Investigator(Kenkyū-buntansha): Shiraki Makoto 岐阜大学, 医学部附属病院, 講師 (60402195) ; 森脇 久隆 岐阜大学, 医学(系)研究科(研究院), 教授 (50174470)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肥満 / 糖尿病 / 肝発癌抑制 / 非アルコール性脂肪肝炎 / 生活習慣病

Outline of Final Research Achievements

Hepatocellular carcinoma (HCC) is one of the most common malignancies affected by obesity. Our study indicates the possibility that pharmaceutical and nutraceutical agents, such as pentoxifylline, sodium alginate, metformin and astaxanthin, for targeting and restoring metabolic disorders, especially activation of renin-angiotensin system, oxidative stress and chronic inflammation, may be an effective strategy for preventing the development of obesity-, diabetes- and nonalcoholic steatohepatitis-related HCC and improving the prognosis of this malignancy.
Our study also shows the evidence that sarcopenia (the loss of skeletal muscle mass) is significantly involved in mortality in patients with HCC and liver cirrhosis especially who have obese. Therefore, prevention of sarcopenia might be associated with improved survival of such patients.

Research Products

• [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] 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 XY, Tatsukawa H, Hitomi K, Shirakami Y, Ishibashi N, Shimizu M, Moriwaki H, Kojima S.
  • Journal Title: Cancer Prev Res Volume: 9 Pages: 205-14
  • 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] 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] The Dipeptidyl Peptidase-4 Inhibitor Teneligliptin Attenuates Hepatic Lipogenesis via AMPK Activation in Non-Alcoholic Fatty Liver Disease Model Mice. (2015)
  • Author(s): Ideta T, Shirakami Y, Miyazaki T, Kochi T, Sakai H, Moriwaki H, Shimizu M.
  • Journal Title: Int J Mol Sci. Volume: 16(12) Issue: 12 Pages: 29207-29218
  • DOI: 10.3390/ijms161226156
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
• [Journal Article] Skeletal muscle depletion predicts the prognosis of patients with hepatocellular carcinoma treated with sorafenib. (2015)
  • Author(s): Imai K, Takai K, Hanai T, Ideta T, Miyazaki T, Kochi T, Suetsugu A, Shiraki M, Shimizu M.
  • Journal Title: Int J Mol Sci Volume: 16 Issue: 5 Pages: 9612-9624
  • DOI: 10.3390/ijms16059612
  • Peer Reviewed
• [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] Metformin suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-+Leprdb/+Leprdb mice. (2015)
  • Author(s): Shimizu M, Ohno T, Shirakami Y, Baba A, Kochi T, Kubota M, Tsurumi H, Tanaka T, Moriwaki H.
  • Journal Title: PLoS One Volume: 10 Issue: 4 Pages: e0124081-e0124081
  • DOI: 10.1371/journal.pone.0124081
  • Peer Reviewed / Open Access
• [Journal Article] Sarcopenia impairs prognosis of patients with liver cirrhosis. (2015)
  • Author(s): Hanai T, Shiraki M, Nishimura K, Ohnishi S, Imai K, Suetsugu A, Takai K, Shimizu M, Moriwaki H.
  • Journal Title: Nutrition Volume: 31 Issue: 1 Pages: 193-199
  • DOI: 10.1016/j.nut.2014.07.005
  • Peer Reviewed
• [Journal Article] Skeletal muscle depletion is an independent prognostic factor for hepatocellular carcinoma. (2015)
  • Author(s): Iritani S, Imai K, Takai K, Hanai T, Ideta T, Miyazaki T, Suetsugu A, Shiraki M, Shimizu M, Moriwaki H.
  • Journal Title: J Gastroenterol Volume: 50 Issue: 3 Pages: 323-332
  • DOI: 10.1007/s00535-014-0964-9
  • Peer Reviewed
• [Journal Article] A newly synthesized compound, 4'-geranyloxyferulic acid-N(omega)-nitro-l-arginine methyl ester suppresses inflammation-associated colorectal carcinogenesis in male mice. (2014)
  • Author(s): Shimizu M, Kochi T, Shirakami Y, Genovese S, Epifano F, Fiorito S, Mori T, Tanaka T, Moriwaki H.
  • Journal Title: Int J Cancer Volume: 135 Issue: 4 Pages: 774-784
  • DOI: 10.1002/ijc.28718
  • Peer Reviewed
• [Journal Article] Impact of serum chemerin levels on liver functional reserves and platelet counts in patients with hepatocellular carcinoma. (2014)
  • Author(s): Imai K, Takai K, Hanai T, Shiraki M, Suzuki Y, Hayashi H, Naiki T, Nishigaki Y, Tomita E, Shimizu M, Moriwaki H.
  • Journal Title: Int J Mol Sci Volume: 15 Issue: 7 Pages: 11294-11306
  • DOI: 10.3390/ijms150711294
  • Peer Reviewed / Open Access
• [Journal Article] Combination of Bevacizumab and Acyclic Retinoid Inhibits the Growth of Hepatocellular Carcinoma Xenografts (2014)
  • Author(s): Kubota M, Shimizu M, Baba A, Ohno T, Kochi T, Shirakami Y, Moriwaki H.
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 60 Issue: 5 Pages: 357-362
  • DOI: 10.3177/jnsv.60.357
  • NAID: 130004773635
  • ISSN: 0301-4800, 1881-7742
  • Peer Reviewed
• [Journal Article] Preventive effects of captopril, an angiotensin-converting enzyme inhibitor, on the development of azoxymethane-induced colonic preneoplastic lesions in diabetic and hypertensive rats. (2014)
  • Author(s): Kochi T, Shimizu M, Ohno T, Baba A, Sumi T, Kubota M, Shirakami Y, Tsurumi H, Tanaka T, Moriwaki H.
  • Journal Title: Oncol Lett Volume: 8 Pages: 223-229
  • Peer Reviewed
• [Journal Article] A novel aromatic mutagen, 5-amino-6-hydroxy-8H-benzo [6,7] azepino [5,4,3-de] quinolin-7-one (ABAQ), induces colonic preneoplastic lesions in mice. (2014)
  • Author(s): Kochi T, Shimizu M, Totsuka Y, Shirakami Y, Nakanishi T, Watanabe T, Tanaka T, Nakagama H, Wakabayashi K, Moriwaki H.
  • Journal Title: Toxicology Rep Volume: 1 Pages: 69-73
  • Peer Reviewed
• [Journal Article] Pharmaceutical and nutraceutical approaches for preventing liver carcinogenesis: chemoprevention of hepatocellular carcinoma using acyclic retinoid and branched-chain amino acids. (2014)
  • Author(s): Shimizu M, Shirakami Y, Hanai T, Imai K, Suetsugu A, Takai K, Shiraki M, Moriwaki H.
  • Journal Title: Mol Nutr Food Res. Volume: 58 Issue: 1 Pages: 124-135
  • DOI: 10.1002/mnfr.201300538
  • Peer Reviewed
• [Journal Article] Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. (2014)
  • Author(s): Ohnishi K, Semi K, Yamamoto T, Shimizu M, Tanaka A, Mitsunaga K, Okita K, Osafune K, Arioka Y, Maeda T, Soejima H, Moriwaki H, Yamanaka S, Woltjen K, Yamada Y.
  • Journal Title: Cell Volume: 156 Issue: 4 Pages: 663-677
  • DOI: 10.1016/j.cell.2014.01.005
  • Peer Reviewed
• [Journal Article] Non-alcoholic steatohepatitis and preneoplastic lesions develop in the liver of obese and hypertensive rats: Suppressing effects of EGCG on the development of liver lesions. (2014)
  • Author(s): Kochi T, Shimizu M, Terakura D, Baba A, Ohno T, Kubota M, Shirakami Y, Tsurumi H, Tanaka T, Moriwaki H.
  • Journal Title: Cancer Lett Volume: 342 Issue: 1 Pages: 60-69
  • DOI: 10.1016/j.canlet.2013.08.031
  • Peer Reviewed
• [Journal Article] Free fatty acid as a marker of energy malnutrition in liver cirrhosis. (2013)
  • Author(s): Hanai T, Shiraki M, Nishimura K, Imai K, Suetsugu A, Takai K, Shimizu M, Naiki T, Moriwaki H.
  • Journal Title: Hepatol Res. Volume: 44 Issue: 2 Pages: 218-228
  • DOI: 10.1111/hepr.12112
  • Peer Reviewed
• [Journal Article] Chemical-induced Carcinogenesis. (2013)
  • Author(s): Tanaka T, Shimizu M, Moriwaki H.
  • Journal Title: J Exp Clin Med Volume: 5 Pages: 203-209
  • Peer Reviewed
• [Journal Article] Hepatocellular carcinoma patients with increased oxidative stress levels are prone to recurrence after curative treatment: a prospective case series study using the d-ROM test. (2013)
  • Author(s): Suzuki Y, Imai K, Takai K, Hanai T, Hayashi H, Naiki T, Nishigaki Y, Tomita E, Shimizu M, Moriwaki H.
  • Journal Title: J Cancer Res Clin Oncol Volume: 139 Issue: 5 Pages: 845-852
  • DOI: 10.1007/s00432-013-1389-1
  • Peer Reviewed
• [Journal Article] (－)-Epigallocatechin-3-gallate suppresses hepatic preneoplastic lesions developed in a novel rat model of non-alcoholic steatohepatitis. (2013)
  • Author(s): Sumi T, Shirakami Y, Shimizu M, Kochi T, Ohno T, Kubota M, Shiraki M, Tsurumi H, Tanaka T, Moriwaki H.
  • Journal Title: SpringerPlus Volume: 2 Pages: 690-690
  • Peer Reviewed
• [Journal Article] The effect of acyclic retinoid on the metabolomic profiles of hepatocytes and hepatocellular carcinoma cells (2013)
  • Author(s): Xian-Yang Qin, Feifei Wei, Masaru Tanokura, Naoto Ishibashi, Masahito Shimizu, Hisataka Moriwaki, Soichi Kojima
  • Journal Title: PLoS ONE Volume: 8 Issue: 12 Pages: e82860-e82860
  • DOI: 10.1371/journal.pone.0082860
  • Peer Reviewed
• [Journal Article] Enhanced development of azoxymethane-induced colonic preneoplastic lesions in hypertensive rats. (2013)
  • Author(s): Takahiro Kochi, Masahito Shimizu, Tomohiko Ohno, Atsushi Baba, Takafumi Sumi, Masaya Kubota, Yohei Shirakami, Hisashi Tsurumi, Takuji Tanaka, and Hisataka Moriwaki
  • Journal Title: Int. J. Mol. Sci. Volume: 14 Issue: 7 Pages: 14700-14711
  • DOI: 10.3390/ijms140714700
  • Peer Reviewed
• [Journal Article] Effects of indoleamine 2, 3-dioxygenase deficiency on high-fat diet-induced hepatic inflammation (2013)
  • Author(s): Nagano J, Shimizu M, Hara T, Shirakami Y, Kochi T, Nakamura N, Ohtaki H, Ito H, Tanaka T, Tsurumi H, Saito K, Seishima M, Moriwaki H
  • Journal Title: PLoS One Volume: 9;8(9) Issue: 9 Pages: e73404-e73404
  • DOI: 10.1371/journal.pone.0073404
  • Peer Reviewed
• [Journal Article] Synergistic growth inhibition by acyclic retinoid and phosphatidylinositol 3-kinase inhibitor in human hepatoma cells. (2013)
  • Author(s): Baba A, Shimizu M, Ohno T, Shirakami Y, Kubota M, Kochi T, Terakura D, Tsurumi H, Moriwaki H.
  • Journal Title: BMC Cancer Volume: 13 Issue: 1 Pages: 465-465
  • DOI: 10.1186/1471-2407-13-465
  • Peer Reviewed
• [Presentation] The role of the phosphorylated RXR-alpha on diethylnitrosamine-induced liver tumorigenesis in mice. (2015)
  • Author(s): Sakai H, Yamada Y, Shirakami Y, Hara A, Shimizu M.
  • Organizer: The 3rd International Conference on Retinoids
  • Place of Presentation: 岐阜
  • Year and Date: 2015-10-21
  • Int'l Joint Research
• [Presentation] 肝硬変における骨格筋変化率が予後に及ぼす影響についての検討 (2015)
  • Author(s): 華井竜徳、白木 亮、大西祥代、森脇久隆、清水雅仁
  • Organizer: JDDW2015（第19回日本肝臓学会大会）
  • Place of Presentation: 東京
  • Year and Date: 2015-10-09
• [Presentation] Prevention of lifestyle disease-related gastroenterological carcinogenesis through regulation of oxidative stress. (English Session) (2015)
  • Author(s): Kochi T, Shirakami Y, Shimizu M
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-09
• [Presentation] DPP4阻害薬テネリグリプチンのNAFLDモデルマウスにおける効果 (2015)
  • Author(s): 出田貴康、白上洋平、宮崎恒起、河内隆宏、境 浩康、清水雅仁
  • Organizer: JDDW 2015（第19回日本肝臓学会大会）
  • Place of Presentation: 東京
  • Year and Date: 2015-10-08
• [Presentation] The role of the phosphorylated RXR-alpha on diethylnitrosamine-induced liver tumorigenesis in mice. (2015)
  • Author(s): Sakai H, Yamada Y, Shirakami Y, Hara A, and Shimizu M.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] 肥満関連肝発癌におけるアスタキサンチンの抑制効果 (2015)
  • Author(s): 出田貴康、大野智彦、宮崎恒起、河内隆宏、白上洋平、清水雅仁
  • Organizer: がん予防学術大会2015（第22回日本がん予防学会総会）
  • Place of Presentation: 埼玉
  • Year and Date: 2015-06-06
• [Presentation] NAFLDモデルマウスにおけるDPP4阻害薬テネリグリプチンの影響 (2015)
  • Author(s): 出田貴康、白上洋平、宮崎恒起、河内隆宏、境 浩康、清水雅仁
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2015-05-21
• [Presentation] NAFLD/NASHモデルマウスにおいてDPP4阻害薬テネリグリプチンは肝脂肪化を抑制する (2015)
  • Author(s): 出田貴康、白上洋平、宮崎恒起、河内隆宏、境 浩康、清水雅仁
  • Organizer: 第101回日本消化器病学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2015-04-25
• [Presentation] シンポジウム12-2「ストレスと消化器疾患」 酸化ストレスの制御を介した生活習慣病関連消化器発癌の抑制 (2015)
  • Author(s): 清水雅仁、河内隆宏、白上洋平
  • Organizer: 第101回日本消化器病学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2015-04-23
• [Presentation] アスタキサンチンによる肥満関連肝・大腸発癌の抑制効果 (2015)
  • Author(s): 河内隆宏、白上洋平、出田貴康、宮崎恒起、清水雅仁
  • Organizer: 第101回日本消化器病学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2015-04-23
• [Presentation] Preventive effects of branched-chain amino acid supplementation on the spontaneous development of hepatic preneoplastic lesions in C57BL/KsJ-db/db obese mice. (2015)
  • Author(s): Ideta T, Terakura D, Shimizu M, Miyazaki T, Kochi T, Sakai H, Shirakami Y, Tanaka T, Moriwaki H.
  • Organizer: 106th American Association for Cancer Research (AACR) Annual Meeting
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-21
  • Int'l Joint Research
• [Presentation] The role of the phosphorylated RXR-alpha on cellular proliferation and liver tumorigenesis. (2015)
  • Author(s): Sakai H, Shirakami Y, Shimizu M, and Moriwaki H
  • Organizer: 106th American Association for Cancer Research (AACR) Annual Meeting
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-20
  • Int'l Joint Research
• [Presentation] 日本人の肝硬変におけるCTとInbodyの相関性 岐阜大学の事例 (2015)
  • Author(s): 白木 亮、大西祥代、華井竜徳、清水雅仁
  • Organizer: 肝とサルコペニアを考える会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-04
• [Presentation] ワークショップ8「生活習慣と肝病態の変遷：明日の肝臓病学に向けて」 生活習慣病治療薬を用いた肥満・糖尿病関連肝発癌の抑制 (2014)
  • Author(s): 清水雅仁 森脇久隆
  • Organizer: JDDW2014（第18回日本肝臓学会大会）
  • Place of Presentation: 神戸
  • Year and Date: 2014-10-24
• [Presentation] NASH・肥満関連分子異常を標的とした肝癌再発予測と肝発癌化学予防 (2013)
  • Author(s): 清水雅仁、森脇久隆
  • Organizer: JDDW2013
  • Place of Presentation: 東京
• [Presentation] Preventive effects of branched-chain amino acids supplementation on the spontaneous development of hepatic preneoplastic lesions in C57BL/KsJ-db/db obese mice (2013)
  • Author(s): Shimizu M, Terakura D, Kochi T, Ohno T, Kubota M, Shirakami Y, Tanaka T, Moriwaki H
  • Organizer: 104th AACR (American Association for Cancer Research) Annual Meeting
  • Place of Presentation: Washington, DC, USA
• [Presentation] Chemoprevention of obesity- and diabetes-related liver carcinogenesis by branched-chain amino acids and acyclic retinoid (2013)
  • Author(s): Shimizu M, Moriwaki H
  • Organizer: The 3rd AACR International Conference on Frontiers in Basic Cancer Research
  • Place of Presentation: National Harbor, MD, USA
• [Presentation] ワークショップ「炎症および傷害物質に関連した発がんと予防」肝および内臓脂肪の炎症制御を介した分岐鎖アミノ酸によるNAFLD関連肝腫瘍形成の抑制 (2013)
  • Author(s): 清水雅仁、寺倉大志、河内隆宏、白上洋平、田中卓二、森脇久隆
  • Organizer: 第20回日本がん予防学会
  • Place of Presentation: 東京
• [Presentation] ワークショップ「炎症および傷害物質に関連した発がんと予防」 非アルコール性脂肪肝炎関連肝発癌新規モデルとペントキシフィリンによる発癌抑制効果 (2013)
  • Author(s): 白上洋平、清水雅仁、森脇久隆、清島満
  • Organizer: 第20回日本がん予防学会
  • Place of Presentation: 東京
• [Presentation] シンポジウム「レチノイド研究温故知新―レチノイドの新たな作用点を求めて―」 非環式レチノイドによる肝発癌化学予防 ―Chemoprevention of hepatocellular carcinoma by acyclic retinoid― (2013)
  • Author(s): 清水雅仁、森脇久隆
  • Organizer: 日本レチノイド研究会第24回学術集会
  • Place of Presentation: 東京
  • Invited
• [Presentation] パネルディスカッション1「C型肝炎を背景とした肝細胞癌―予防から再発治療まで―」 非環式レチノイドと分岐鎖アミノ酸を用いた肝発癌抑制―肥満関連肝発癌抑制と両剤の併用投与による相乗的肝癌細胞増殖抑制― (2013)
  • Author(s): 清水雅仁、白上洋平、森脇久隆
  • Organizer: JDDW2013
  • Place of Presentation: 東京