Analysis of metabolic reprogramming induced by cellular environment and its application to control hepato-carcinogenesis

• Project/Area Number: 18H02798
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kumamoto University
• Principal Investigator: SASAKI YUTAKA 熊本大学, 大学院生命科学研究部(医), 名誉教授 (70235282)
• Co-Investigator(Kenkyū-buntansha): 長岡 克弥 熊本大学, 病院, 助教 (00759524) ; 渡邊 丈久 熊本大学, 大学院生命科学研究部(医), 助教 (20634843) ; 直江 秀昭 熊本大学, 病院, 講師 (30599246) ; 荒木 令江 熊本大学, 大学院生命科学研究部(医), 准教授 (80253722) ; 藤元 治朗 兵庫医科大学, 医学部, 特別招聘教授 (90199373)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2019: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
• Keywords: 肝癌 / 細胞環境 / 代謝リプログラミング / 治療抵抗性 / 分子標的治療薬 / 効果予測マーカー / エピジェネテイクス / オミクス解析 / マルチオミクス解析 / メタボローム解析 / 肝発癌 / 原発性肝癌 / メタボローム / メダボローム解析

Outline of Final Research Achievements

When gene expression in response to Sorafenib (SFN), a molecular target agent for HCCs, was compared between HepG2 cells and HepG2- SFN resistant cells (HepG2-SR), genes in the metabolism of lipids were significantly enriched in both cell lines, whereas gene expressions by SREBP1C were significantly enhanced in HepG2-SR cells. Clusterin (CLU), one of the target genes of SREBP1C, was up-regulated in HepG2-SR cells and knock-down with siRNA enhanced SFN treatment response, suggesting that CLU might play a role in SFN resistance. In addition, an increase in serum CLU level one month after SFN treatment initiation was significantly associated with shorter PFS in the HCC patients, indicating that serum CLU might be a potential biomarker for early prediction of SFN response. On the other hand, hypoxia or high fat microenvironment enhanced expression of LSD1 and LSD2, histone demethylase, in hepatoma cell lines, leading to lipid and carbohydrate reprogramming required for cancer cell growth.

Academic Significance and Societal Importance of the Research Achievements

低酸素環境、分子標的治療薬存在下などの細胞環境に肝癌細胞は適応し、代謝リプログラミングとして細胞内の代謝を変化させ、さらに治療抵抗性を獲得して増殖進展を続ける。そこで本研究では、さまざまな細胞環境下で誘導されるエピゲノム制御分子（遺伝子発現を調節する分子）とそれによりもたらされる代謝変化を明らかにしたことで、代謝リプログラミングの制御を介した新たな治療法に発展することが期待される。さらに分子標的治療薬が代謝リプログラミングを介して誘導する治療抵抗性分子を同定し、治療効果の早期予測血清マーカーとしての有用性を証明したため、今後、肝癌の治療法選択に応用される可能性がある。

Research Products

• [Journal Article] Predictors of hepatocellular carcinoma recurrence associated with the use of direct-acting antiviral agent therapy for hepatitis C virus after curative treatment: A prospective multicenter cohort study. (2019)
  • Author(s): Nakano M, Koga H, Ide T, Kuromatsu R, Hashimoto S, Yatsuhashi H, Seike M, Higuchi N, Nakamuta M, Shakado S, Sakisaka S, Miuma S, Nakao K, Yoshimaru Y, Sasaki Y, Oeda S, Eguchi Y, Honma Y, Harada M, Nagata K, Mawatari S, Ido A, Maeshiro T, Matsumoto S, Takami Y, Sohda T, Torimura T
  • Journal Title: Cancer Medicine Volume: 印刷中 Pages: 2646-2653
  • DOI: 10.1002/cam4.2061
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Direct-acting antiviral agents do not increase the incidence of hepatocellular carcinoma development: a prospective, multicenter study (2019)
  • Author(s): Ide T, Koga H, Nakano M, Hashimoto S, Yatsuhashi H, Higuchi N, Nakamuta M, Oeda S, Eguchi Y, Shakado S, Sakisaka S, Yoshimaru Y, Sasaki Y, Honma Y, Harada M, Seike M, Maeshiro T, Miuma S, Nakao K, Mawatari S, Ido A, Nagata K, Matsumoto S, Takami Y, Sohda T, Kakuma T, Torimura T
  • Journal Title: Hepatology International Volume: 印刷中 Pages: 293-301
  • DOI: 10.1007/s12072-019-09939-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: Journal of Gastroenterology Volume: 54 Pages: 367-376
  • DOI: 10.1007/s00535-018-1532-5
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Fusion of Type-I Interferon to a Recombinant Albumin Mutant with polymannosylated N-linked oligosaccharide attached is a Novel and Superior Kupffer Cell Targeting Agent for the Treatment of Hepatitis. (2018)
  • Author(s): Minayoshi Y, Maeda H, Yanagisawa H, Hamasaki K, Mizuta Y, Nishida K, Kinoshita R, Enoki Y, Imafuku T, Chuang VTG, Koga T, Fujiwara Y, Takeya M, Sonoda K, Wakayama T, Taguchi K, Ishima Y, Ishida T, Iwakiri Y, Tanaka M, Sasaki Y, Watanabe H, Otagiri M, Maruyama T.
  • Journal Title: Drug Deliv. Volume: 25 Pages: 1055-1065
  • DOI: 10.1080/10717544.2018.1464083
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial (2018)
  • Author(s): Kudo M、Ueshima K、Yokosuka O、Ogasawara S、Obi S、Izumi N、Aikata H、Nagano H、Hatano E、Sasaki Y、Hino K、Kumada T、Yamamoto K、Imai Y、Iwadou S、Ogawa C、Okusaka T、Kanai F、Akazawa K、Yoshimura K、Johnson P、Arai Y
  • Journal Title: Lancet Gastroenterol Hepatol. 2018 Jun;3(6):424-432 Volume: 3 Pages: 424-432
  • DOI: 10.1016/s2468-1253(18)30078-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Prognostic Factors in Patients with Advanced HCC Receiving Sorafenib or Hepatic Arterial Infusion Chemotherapy (2018)
  • Author(s): Motohiko Tanaka, Takayuki Tokunaga, Kentaro Tanaka, Satoshi Narahara, Takeshi Kawasaki, Yoko Yoshimaru, Takehisa Watanabe, Masakuni Tateyama, Hideaki Naoe, Yutaka Sasaki
  • Organizer: The Asian Pacific Association for the Study of the Liver
  • Int'l Joint Research
• [Presentation] Treatment Strategy Based on Sorafenib for Advanced Hepatocellular Carcinoma (2018)
  • Author(s): Takayuki Tokunaga,Motohiko Tanaka,Kentaro Tanaka,Satoshi Narahara,Youko Yoshimaru,Katsuya Nagaoka,Takeshi Kawasaki,Hiroko Setoyama,Takehisa Watanabe,Masakuni Tateyama and Yutaka Sasaki
  • Organizer: The Liver Meeting 2018 - AASLD
  • Int'l Joint Research
• [Presentation] Early Prediction of Sorafenib Response in Patients with Hepatocellular Carcinoma: The Possible Role of Secretory Clusterin in Acquired Sorafenib Resistance. (2018)
  • Author(s): Satoshi Narahara,Takehisa Watanabe,Katsuya Nagaoka,Nahoko Fujimoto,Kentaro Tanaka,Takayuki Tokunaga,Takeshi Kawasaki,Youko Yoshimaru,Hiroko Setoyama,Masakuni Tateyama,Hideaki Naoe,Motohiko Tanaka and Yutaka Sasaki
  • Organizer: The Liver Meeting 2018 - AASLD
  • Int'l Joint Research
• [Presentation] 進行肝細胞癌に対するソラフェニブ治療と肝動注化学療法の効果解析から検討する治療戦略 (2018)
  • Author(s): 徳永尭之、田中基彦、佐々木裕
  • Organizer: 第104回日本消化器病学会総会
• [Presentation] 肝細胞癌に対するソラフェニブの治療効果を早期に予測する新規血清バイオマーカーの解析 (2018)
  • Author(s): 楢原哲史、渡邊丈久、田中健太郎、徳永尭之、川崎剛、吉丸洋子、立山雅邦、田中基彦、佐々木裕
  • Organizer: 第54回日本肝臓学会総会
• [Book] 最新ガイドライン準拠消化器疾患 診断・治療指針 (2018)
  • Author(s): 佐々木裕、木下芳一、下瀬川徹、渡辺 守
  • Total Pages: 480
  • Publisher: 中山書店
  • ISBN: 9784521746012