肝微小環境において炎症性発がんを制御するantagomirの標的創薬と前臨床試験

• 研究課題/領域番号: 22390149
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 消化器内科学
• 研究機関: 福井大学
• 研究代表者: 中本 安成 福井大学, 医学部, 教授 (40293352)
• 研究分担者: 山下 太郎 金沢大学, 大学病院, 助教 (90377432)
• 研究期間 (年度): 2010 – 2012
• 研究課題ステータス: 完了 (2012年度)
• 配分額: 18,070千円 (直接経費: 13,900千円、間接経費: 4,170千円); 2012年度: 4,940千円 (直接経費: 3,800千円、間接経費: 1,140千円); 2011年度: 5,850千円 (直接経費: 4,500千円、間接経費: 1,350千円); 2010年度: 7,280千円 (直接経費: 5,600千円、間接経費: 1,680千円)
• キーワード: 癌 / 遺伝子 / 核酸 / 動物 / 内科

研究概要

慢性肝炎から肝細胞がん (肝がん) に至る微小環境において、マイクロ RNA に対して制御効果を発揮する核酸分子(antagomir)の標的創薬を目的とした。B型慢性肝炎モデルで同定された8個のマイクロ RNA について、経時的肝組織における発現解析、形質転換作用の検討、宿主遺伝子の発現調節作用、がん化に関わる分子病態おける評価を実施した。これより、本研究のマイクロ RNA が肝がんを制御する antagomir 創薬における標的となる可能性が示された。

研究成果

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• [雑誌論文] Transcriptomic profiling reveals hepatic stem-like gene signatures and interplay of miR-200c and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma (2012)
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  • 雑誌名: HEPATOLOGY 巻: 56 ページ: 1792-1803
  • 査読あり
• [雑誌論文] Clinical relevance and sequence analysis of the Helicobacter pylori dupA region from two areas in Japan with different gastric cancer risks. (2012)
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  • 雑誌名: Immuno-Gatroenterology 巻: 1 ページ: 127-135
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• [雑誌論文] Membrane-bound form of monocyte chemoattractant protein-1 enhances antitumor effects of suicide gene therapy in a model of hepatocellular carcinoma. (2012)
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  • 雑誌名: Cancer Gene Ther. 巻: 19(5) 号: 5 ページ: 312-319
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• [雑誌論文] Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma (2011)
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  • 雑誌名: HEPATOLOGY 巻: 53 ページ: 1206-1216
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• [雑誌論文] Frequency of CD45RO+ subset in CD4+CD25(high) regulatory T cells associated with progression of hepatocellular carcinoma (2011)
  • 著者名/発表者名: Takata Y, Nakamoto Y, Nakada A, Terashima T, Arihara F, Kitahara M, Kakinoki K, Arai K, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Kaneko S
  • 雑誌名: Cancer Lett 巻: 307 ページ: 165-173
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• [雑誌論文] Hokuriku Liver Study Group: Malnutrition impairs interferon signaling through mTOR and FoxO pathways in patients with chronic hepatitis C (2011)
  • 著者名/発表者名: Honda M, Takehana K, Sakai A, Tagata Y, Shirasaki T, Nishitani S, Muramatsu T, Yamashita T, Nakamoto Y, Mizukoshi E, Sakai Y, Yamashita T, Nakamura M, Shimakami T, Yi M, Lemon SM, Suzuki T, Wakita T, Kaneko S
  • 雑誌名: GASTROENTEROLOGY 巻: 141 ページ: 128-140
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• [雑誌論文] Randomized, phase II study comparing interferon combined with hepatic arterial infusion of fluorouracil plus cisplatin and fluorouracil alone in patients with advanced hepatocellular carcinoma. (2011)
  • 著者名/発表者名: Yamashita T, Arai K, Sunagozaka H, Ueda T, Terashima T, Yamashita T, Mizukoshi E, Sakai A, Nakamoto Y, Honda M, Kaneko S
  • 雑誌名: Oncology 巻: 81 ページ: 281-290
  • NAID: 120003674297
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• [雑誌論文] Frequency of CD45RO(+) subset in CD4(+)CD25(high) regulatory T cells associated with progression of hepatocellular carcinoma (2011)
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  • 雑誌名: Cancer Lett. 巻: 307 ページ: 165-173
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• [雑誌論文] Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma (2011)
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  • 雑誌名: Hepatology 巻: 53(4) 号: 4 ページ: 206-16
  • DOI: 10.1002/hep.24149
  • 査読あり
• [雑誌論文] Prolonged recurrence-free survival following OK432-stimulated dendritic cell transfer into hepatocellular carcinoma during transarterial embolization (2011)
  • 著者名/発表者名: Nakamoto Y, Mizukoshi E, Kitahara M, Arihara F, Sakai Y, Kakinoki K, Fujita Y, Marukawa Y, Arai K, Yamashita T, Mukaida N, Matsushima K, Matsui O, and Kaneko S
  • 雑誌名: Clin Exp Immunol 巻: 163(2) 号: 2 ページ: 165-177
  • DOI: 10.1111/j.1365-2249.2010.04246.x
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• [雑誌論文] Prevention of intrahepatic metastasis of liver cancer by suicide gene therapy and chemokine ligand 2/monocyt e chemoattractant protein-1 delivery in mice (2010)
  • 著者名/発表者名: Kakinoki K, Nakamoto Y, Kagaya T, Tsuchiyama T, Sakai Y, Nakahama T, Mukaida N, Kaneko S
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• [雑誌論文] Antitumor effect after radio-frequency ablation of murine hepatoma is augmented by an active variant of cc chemokine ligand 3/macrophage inflammatory protein -1alpha (2010)
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• [雑誌論文] Differential gene expression profiling in blood from patients with digestive system cancers (2010)
  • 著者名/発表者名: Honda M, Sakai Y, Yamashita T, Yamashita T, Sakai A, Mizukoshi E, Nakamoto Y, Tatsumi I, Miyazaki Y, Tanno H, Kaneko S; Hokuriku Liver Study Group
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• [雑誌論文] Oncostatin m renders epithelial cell adhesion molecule-positive liver cancer stem cells sensitive to 5-Fluorouracil by inducing hepatocytic differentiation (2010)
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• [雑誌論文] Enhancement of tumor-specific T -cell responses by transcatheter arterial embolization with dendritic cell infusion for hepatocellular carcinoma (2010)
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• [雑誌論文] Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver (2010)
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• [雑誌論文] A liver-derived secretory protein, selenoprotein P, causes insulin resistance (2010)
  • 著者名/発表者名: Misu H, Takamura T, Takayama H, Hayashi H, Matsuzawa-Nagata N, Kurita S, Ishikura K, Ando H, Takeshita Y, Ota T, Sakurai M, Yamashita T, Mizukoshi E, Yamashita T, Honda M, Miyamoto K, Kubota T, Kubota N, Kadowaki T, Kim HJ, Lee IK, Minokoshi Y, Saito Y, Takahashi K, Yamada Y, Takakura N, Kaneko S
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• [雑誌論文] Enhancement of tumor-specific T-cell responses by transcatheter arterial embol ization with dendritic cell infusion for hepatoc ellular carcinoma. (2010)
  • 著者名/発表者名: Mizukoshi E, Nakamoto Y, Araik, Yamashita T, et al.
  • 雑誌名: Int.J.Cancer 巻: 126 ページ: 2164-2174
  • 査読あり
• [雑誌論文] Antitumor effect after radio-frequency ablation of murine hepat oma is augmented by an active variant of cc chemokine ligand 3/ macrophage inflammatory protein-lalpha. (2010)
  • 著者名/発表者名: IidaN, Nakamoto Y, et al.
  • 雑誌名: Cancer Res. 巻: 70 ページ: 6556-6565
  • 査読あり
• [雑誌論文] Prevention of intrahepatic metastasis of hepatocellular carcinoma by combination of suicide gene therapy and monocyte chemoatt ractant proteinl delivery in mice. (2010)
  • 著者名/発表者名: Kakinoki K, Nakamoto Y, et al.
  • 雑誌名: J.Gene Med. 巻: 12 ページ: 1002-1013
  • 査読あり
• [学会発表] MicroRNA Dynamics in Precancerous Lesions in a Mouse Model of Chronic Hepatitis B (2012)
  • 著者名/発表者名: Nakamoto Y, Yamashita T, Kaneko S
  • 学会等名: 第63回 American Association for the Study of Liver Diseases (AASLD) Annual Meeting
  • 発表場所: Boston, Massachusetts, U.S.A
  • 年月日: 2012-11-13
• [学会発表] High Incidence of HBV Reactivation after R-CHOP and CHOP Regimens among Patients Treated with Six Immunosuppressive Chemotherapies (2012)
  • 著者名/発表者名: Naito T, Nemoto T, Matsuda H, Ohtani M, Suto H Nakamoto Y
  • 学会等名: 第63回American Association for the Study of Liver Diseases (AASLD) Annual Meeting
  • 発表場所: Boston, Massachusetts, U.S.A
  • 年月日: 2012-11-11
• [学会発表] Differential Dynamics of the NF-kappaB subunits RELA and RELB in a Mouse Model of Chronic Hepatitis B (2011)
  • 著者名/発表者名: Nakamoto Y, Yamashita T, Kaneko S
  • 学会等名: 第62回 American Association for the Study of Liver Diseases (AASLD) Annual Meeting
  • 発表場所: San Francisco, California, U.S.A
  • 年月日: 2011-11-08
• [学会発表] Increase of CD14+HLA-DR-/low myeloid-derived suppressor cells in hepatocellular carcinoma and its impact forprognosis of patients (2011)
  • 著者名/発表者名: Arihara F, Mizukoshi E, Kitahara M, Takata Y, Arai K, Yamashita T, Nakamoto Y, Kaneko S
  • 学会等名: 第62回 American Association for the Study of Liver Diseases (AASLD) Annual Meeting
  • 発表場所: San Francisco, California, U.S.A
  • 年月日: 2011-11-08
• [学会発表] Differential Dynamics of the NF-kappaB subunits RELA and RELB in a Mouse Model of Chronic Hepatitis B (2011)
  • 著者名/発表者名: Nakamoto Y, Yamashita T, Kaneko S
  • 学会等名: 第62回American Association for the Study of Liver Diseases (AASLD) Annual Meeting
  • 発表場所: San Francisco, California (USA)
  • 年月日: 2011-11-08
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  • 著者名/発表者名: Nakamoto Y, Yamashita T, Kaneko S
  • 学会等名: 第61回American Association for the Study of Liver Diseases (AASLD) Annual Meeting
  • 発表場所: Boston, Massachusetts, U.S.A
  • 年月日: 2010-11-01
• [学会発表] #1268 ; NFkB activation precedes dynamics of oxidative stress-related procarcinogenic signalings in a mouse model of chronic he patitis B. (2010)
  • 著者名/発表者名: Nakamoto Y, Yamashita T, et al.
  • 学会等名: 第61回American Association for the Study of Liver Diseases (AASLD) Annual Meeting
  • 発表場所: Boston,Massachusetts(USA)
  • 年月日: 2010-11-01
• [学会発表] Dendritic Cell Transfer during Locoregional Treatments Induces Prolonged Recurrence-Free Survival in Patients with Hepatocellular Carcinoma (2010)
  • 著者名/発表者名: Nakamoto Y, Mizukoshi E, Kitahara M, Arihara F, Sakai Y, Kakinoki K, Fujita Y, Marukawa Y, Arai K, Yamashita T , Mukaida N, Matsushima K, Matsui O, Kaneko S
  • 学会等名: International Symposium on Tumor Biology in Kanazawa "Cancer and Host Response
  • 発表場所: Kanazawa, Japan
  • 年月日: 2010-08-29
• [学会発表] MicroRNA Dynamics in Precancerous Lesions in a Mouse Model of Chronic Hepatitis B.
  • 著者名/発表者名: Nakamoto Y, Yamashita T, Kaneko S
  • 学会等名: 第63回 American Association for the Study of Liver Diseases (AASLD) Annual Meeting
  • 発表場所: Boston, Massachusetts, U.S.A.