Regulation of liver innate immunnity in human hepatocellular carcinoma

• Project/Area Number: 24590973
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: TATSUMI Tomohide 大阪大学, 医学(系)研究科(研究院), 助教 (20397699)
• Co-Investigator(Kenkyū-buntansha): MIYAGI Takuya 大阪大学, 大学院医学系研究科, 助教 (80532986)
• Research Collaborator: NAWA Takatoshi ; AONO Satoshi
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肝細胞癌 / C型肝炎ウイルス / 抗癌剤 / 先天免疫 / 細胞周期 / 肝癌幹細胞 / 低酸素 / 抗がん剤

Outline of Final Research Achievements

The aim of this study is to investigate the cell death of hepatitis C virus (HCV) infected hepatocellular carcinoma (HCC) cells. HCV-infected HCC cells were more resistant to epirubicin and sorafenib than non-infected HCC cells. HCV-infected HCC cells exhibited anti-apoptotic and higher expression of ATP-binding cassette drug transporters. HCV infection resulted in increasing the characteristics of cancer stem cell of HCC. Cell cycle analysis revealed the increase of sub-population of G0/G1 phase in HCV-infected HCC cells. HCV eradication by interferon-alpha treatment resulted in improvement of the efficacy of anti-cancer drug by changing the anti-apoptotic characteristics. These results suggested that eradication of HCV should be required in the treatment of HCC.

Research Products

• [Journal Article] Risk factors for hepatocellular carcinoma in hepatitis C patients with normal ALT treated with pegylated interferon and ribavirin (2014)
  • Author(s): Harada N, Hiramatsu N, Oze T, Morishita N, Yamada R, Hikita H, Miyazaki M, Yakushijin T, Miyagi T, Yoshida Y, Tatsumi T, Kanto A, Kasahara A, Oshita M, Mita E, Hagiwara H, Inui Y, Katayama K, Shinji Tamura, Yoshihara H, Imai Y, Inoue A, Hayashi N, Takehara T
  • Journal Title: J Viral Hepat Volume: ２１ Issue: 5 Pages: 357-365
  • DOI: 10.1111/jvh.12151
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] the Osaka Liver Forum. Post-treatment Levels ofα-fetoprotein Predict Incidence of Hepatocellular Carcinoma After Interferon Therapy (2013)
  • Author(s): Oze T, Yoshida Y,他25人
  • Journal Title: Clin Gastroenterol Hepatol Volume: (Epub ahead of print), (pii : S1542-3565(13)01840-5) Issue: 7 Pages: 1239-45
  • DOI: 10.1016/j.cgh.2013.11.033
  • Peer Reviewed
• [Journal Article] Incidence of hepatocellular carcinoma in HCV-infected patients with normal alanine aminotransferase levels categorized by Japanese treatment guidelines (2013)
  • Author(s): Harada N, Hiramatsu N, Oze T, Yamada R, Kurokawa M, Miyazaki M, Yakushijin T, Miyagi T, Tatsumi T, Kiso S, Kanto T, Kasahara A, Oshita M, Mita E, Hagiwara H, Inui Y, Katayama K, Tamura S, Yoshihara H, Imai Y, Inoue A, Hayashi N, Takehara T
  • Journal Title: J Gastroenterol Volume: 48 Issue: 4 Pages: 535-43
  • DOI: 10.1007/s00535-012-0657-1
  • NAID: 10031169228
  • Peer Reviewed
• [Journal Article] The Bcl-2 homology 3 (BH3)-only proteins Bim and Bid are functionally active and restrained by anti-apoptotic B-cell CLL/lymphoma 2 (Bcl-2) family proteins in healthy liver. (2013)
  • Author(s): [1] Kodama T, Hikita H, Kawaguchi T, Saito Y, Tanaka S, Shigekawa M, Shimizu S, Li W, Miyagi T, Kanto T, Hiramatsu N, Tatsumi T, Takehara T.
  • Journal Title: J. Biol. Chem. Volume: 288 Issue: 42 Pages: 30009-30018
  • DOI: 10.1074/jbc.m112.443093
  • Peer Reviewed
• [Journal Article] Valine, the branched-chain amino acid, suppresses hepatitis C virus RNA replication but promotes infectious particle formation (2013)
  • Author(s): Ishida H, Kato T, Takehana K, Tatsumi T, Hosui A, Nawa T, Kodama T, Shimizu S, Hikita H, Hiramatsu N, Kanto T, Hayashi N, Takehara T
  • Journal Title: Biochem Biophys Res Commun Volume: 437 Issue: 1 Pages: 127-33
  • DOI: 10.1016/j.bbrc.2013.06.051
  • Peer Reviewed
• [Journal Article] The combination therapy of α-galactosylceramide and 5-fluorouracil showed antitumor effect synergistically against liver tumor in mice (2013)
  • Author(s): Aketa H, Tatsumi T, Kohga K, Tsunematsu H, Aono S, Shimizu S, Kodama T, Nawa T, Shigekawa M, Hikita H, Sakamori R, Hosui A, Miyagi T, Hiramatsu N, Kanto T, Hayashi N, Takehara T
  • Journal Title: Int J Cancer Volume: 133 Issue: 5 Pages: 1126-34
  • DOI: 10.1002/ijc.28118
  • Peer Reviewed
• [Journal Article] Interleukin-1β enhances the production of soluble MICA in human hepatocellular carcinoma (2012)
  • Author(s): Kohga K, Tatsumi T, et al.
  • Journal Title: Cancer Immunology, Immunotherapy Volume: 61 Pages: 1425-1432
  • Peer Reviewed
• [Journal Article] Bak deficiency inhibits liver carcinogenesis : A causal link between apoptosis and carcinogenesis (2012)
  • Author(s): Hikita H, Takehara T, et al
  • Journal Title: Journal of Hepatology Volume: (印刷中) Issue: 1 Pages: 92-100
  • DOI: 10.1016/j.jhep.2012.01.027
  • Peer Reviewed
• [Journal Article] Suppression of signal transducers and activators of transcription 1 (STAT1) in hepatocellular carcinoma is associated with tumor progression (2012)
  • Author(s): Hosui A, Tatsumi T, et al.
  • Journal Title: International Journal of Cancer Volume: 131 Issue: 12 Pages: 2774-2784
  • DOI: 10.1002/ijc.27580
  • Peer Reviewed
• [Journal Article] Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages. (2012)
  • Author(s): Kodama T, Hikita H, Kawaguchi T, Shigekawa M, Shimizu S, Hayashi Y, Li W, Miyagi T, Hosui A, Tatsumi T, Kanto T, Hiramatsu N, Kiyomizu K, Tadokoro S, Tomiyama Y, Hayashi N, Takehara T.
  • Journal Title: Cell Death Differ. Volume: 19(11) Issue: 11 Pages: 1856-1869
  • DOI: 10.1038/cdd.2012.88
  • Peer Reviewed
• [Journal Article] Interferon-α suppresses hepatitis B virus enhancer II activity via the protein kinase C pathway (2012)
  • Author(s): Nawa T, Tatsumi T, et al.
  • Journal Title: Virology Volume: 432 Issue: 2 Pages: 452-459
  • DOI: 10.1016/j.virol.2012.07.002
  • Peer Reviewed
• [Journal Article] Pancreatitis STAT3 protects mice against caerulein-induced pancreatitis via PAP1 induction (2012)
  • Author(s): Shigekawa M, Tatsumi T, et al.
  • Journal Title: The American Journal of Pathology Volume: 181 Issue: 6 Pages: 2105-2113
  • DOI: 10.1016/j.ajpath.2012.08.038
  • Peer Reviewed
• [Presentation] Involvement of hepatitis C virus infection in the regulation of chemo-sensitivity of hepatocellular carcinoma cells (2014)
  • Author(s): Nawa T, Tatsumi T, Nishio A, Tawara S, Onishi Y, Aono S, Hayato Hikita H, Sakamori R, Miyagi T, Hiramatsu N, Takehara T
  • Organizer: The American Association fore Study of Liver Diseases
  • Place of Presentation: 米国ボストン市
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] C型慢性肝疾患に対するSimeprevir/PegIFN/Ribavirin併用療法におけるビリルビン上昇とITPA遺伝子多型について (2014)
  • Author(s): 原田直毅、平松直樹、小瀬嗣子、森下直紀、山田涼子、藥師神崇行、佐治雪子、土井喜宣、山田幸則、福井弘幸、林 英二朗、加藤道夫、疋田隼人、宮城琢也、吉田雄一、巽 智秀、笠原彰紀、林 紀夫、竹原徹郎
  • Organizer: JDDW2014 第18回肝臓学会大会
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2014-10-23 – 2014-10-26
• [Presentation] C型肝炎に対するテラプレビル3剤併用療法非著効例におけるシメプレビル3剤併用療法の有効性と耐性変異について (2014)
  • Author(s): 森下直紀、平松直樹、原田直毅、山田涼子、名和誉敏、疋田隼人、小瀬嗣子、藥師神崇行、宮城琢也、吉田雄一、巽 智秀、大川和良、山田 晃、三田英治、伊藤敏文、稲田正巳、今井康陽、加藤道夫、竹原徹郎
  • Organizer: JDDW2014 第18回肝臓学会大会
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2014-10-23 – 2014-10-26
• [Presentation] Genotype1 C型慢性肝炎に対するSimeprevir/Peg-IFN/RBV併用治療の有用性について (2014)
  • Author(s): 小瀬嗣子、平松直樹、藥師神崇行、山田涼子、原田直毅、森下直紀、宮城琢也、吉田雄一、巽 智秀、大川和良、林 紀夫、竹原徹郎
  • Organizer: 肝臓学会総会 (第50回)
  • Place of Presentation: 東京都
  • Year and Date: 2014-05-29 – 2014-05-30
• [Presentation] C型肝炎に対するシメプレビル治療における次世代シークエンサーを用いた耐性変異の検討 (2014)
  • Author(s): 森下直紀、名和誉敏、原田直毅、山田涼子、清水 聡、疋田隼人、小瀬嗣子、藥師神崇行、宮城琢也、吉田雄一、巽 智秀、大川和良、平松直樹、竹原徹郎
  • Organizer: 肝臓学会総会 (第50回)
  • Place of Presentation: 東京都
  • Year and Date: 2014-05-29 – 2014-05-30
• [Presentation] 肝細胞アポトーシスが発生する酸化ストレスの肝発癌に与える影響 (2013)
  • Author(s): 疋田隼人、巽 智秀、宮城琢也、齋藤義修、田中聡司、清水 聡、阪森亮太郎、平松直樹、竹原徹郎
  • Organizer: 肝臓学会総会 (第49回)
  • Place of Presentation: 東京都
• [Presentation] 肝腫瘍に対するα-Galactosylceramideと5-Fluorouracil併用による免疫化学療法の有用性 (2013)
  • Author(s): 明田寛史、巽 智秀、大西良輝、青野悟志、常松日奈子、疋田隼人、阪森亮太郎、宮城琢也、平松直樹、考藤達哉、林 紀夫、竹原徹郎
  • Organizer: 肝臓学会総会 (第49回)
  • Place of Presentation: 東京都
• [Presentation] Hepatitis C virus infection reduces chemo-sensitivity of the hepatocellular carcinoma cells through enhancing cancer stem cell characters. (2013)
  • Author(s): Takatoshi Nawa, Tomohide Tatsumi, Akira Nishio, Seiichi Tawara, Yoshiki Ohnishi, Satoshi Aono, Satoshi Shimizu, Hayato Hikita, Ryotaro Sakamori, Takuya Miyagi, Naoki Hiramatsu, Tetsuo Takehara
  • Organizer: American Association of the Study of Liver Disease 64th
  • Place of Presentation: 米国ワシントンDC
• [Presentation] Oxidative stress induced by continuous hepatocyte apoptosis drives liver carcinogenesis independently of regeneration and DNA methylation status. (2013)
  • Author(s): Hayato Hikita, Tomohide Tatsumi, Yoshinobu Saito, Satoshi Tanaka, Satoshi Shimizu, Wei Li, Ryotaro Sakamori, Takuya Miyagi, Naoki Hiramatsu, Tetsuo Takehara
  • Organizer: American Association of the Study of Liver Disease 64th
  • Place of Presentation: 米国ワシントンDC
• [Presentation] A novel hepato-proliferative effect of carbamazepine during liver regeneration (2013)
  • Author(s): Tsukasa Kawaguchi, Takahiro Kodama, Satoshi Tanaka, Kaori Mukai, Satoshi Aono, Minoru Shigekawa, Satoshi Shimizu, Hayato Hikita, Wei Li, Takuya Miyagi, Naoki Hiramatsu, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: American Association of the Study of Liver Disease 64th
  • Place of Presentation: 米国ワシントンDC
• [Presentation] 肝細胞癌におけるNK活性化レセプターリガンドの発現機構の解析 (2012)
  • Author(s): 甲賀啓介、巽 智秀、竹原徹郎
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 東京都新宿区
• [Presentation] 肝細胞アポトーシスの持続によるマクロファージの活性化と肝発癌 (2012)
  • Author(s): 疋田隼人、巽 智秀、竹原徹郎
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 東京都新宿区
• [Presentation] セルレイン急性膵炎モデルにおいて膵Stat3は保護的に働く (2012)
  • Author(s): 重川 稔、巽 智秀、竹原徹郎
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 東京都新宿区
• [Presentation] NKG2Dリガンド制御による肝癌免疫化学療法の可能性 (2012)
  • Author(s): 巽 智秀、甲賀啓介、竹原徹郎
  • Organizer: 肝臓学会総会 (第48回)
  • Place of Presentation: 石川県金沢市
• [Presentation] 肝細胞p53による肝線維化誘導機構の解析 (2012)
  • Author(s): 小玉尚宏、巽 智秀、竹原徹郎
  • Organizer: 肝臓学会総会 (第48回)
  • Place of Presentation: 石川県金沢市
• [Presentation] Ras経路が活性化されている肝細胞癌においてSTAT3シグナルは有用な治療ターゲットとなりうる (2012)
  • Author(s): 重川 稔、疋田隼人、巽 智秀、他
  • Organizer: 肝臓学会総会 (第48回)
  • Place of Presentation: 石川県金沢市
• [Presentation] 肝細胞のアポトーシスによる酸化ストレス発生と肝発癌 (2012)
  • Author(s): 疋田隼人、巽 智秀、小玉尚宏、他
  • Organizer: 肝臓学会総会 (第48回)
  • Place of Presentation: 石川県金沢市
• [Presentation] ミトコンドリア介在性アポトーシスによる成熟肝細胞の恒常性制御機構の解明 (2012)
  • Author(s): 小玉尚宏、川口 司、巽 智秀、他
  • Organizer: 肝臓学会総会 (第48回)
  • Place of Presentation: 石川県金沢市
• [Presentation] 自己免疫性肝炎におけるNKT細胞の関与 (2012)
  • Author(s): 西尾公美子、宮城琢也、巽 智秀、他
  • Organizer: 肝臓学会総会 (第48回)
  • Place of Presentation: 石川県金沢市
• [Presentation] マウス肝腫瘍に対する抗癌剤による免疫修飾とNK感受性の制御 (2012)
  • Author(s): 明田寛史、巽 智秀、青野悟志、他
  • Organizer: 肝臓学会総会 (第48回)
  • Place of Presentation: 石川県金沢市
• [Presentation] PPARγおよびmir-20bを介したSTAT5-CD36-肝脂肪化の機序の検討 (2012)
  • Author(s): 法水 淳、巽 智秀、竹原徹郎
  • Organizer: 肝臓学会総会 (第48回)
  • Place of Presentation: 石川県金沢市
• [Presentation] 先天性心疾患術後に発症した肝細胞癌の3例 (2012)
  • Author(s): 大西良輝、宮崎昌典、巽 智秀、他
  • Organizer: 肝臓学会総会 (第48回)
  • Place of Presentation: 石川県金沢市
• [Presentation] C型肝炎における肝メチル化の定量的評価 (2012)
  • Author(s): 清水 聡、小瀬嗣子、巽 智秀、他
  • Organizer: 肝臓学会総会 (第48回)
  • Place of Presentation: 石川県金沢市
• [Presentation] 抗てんかん薬カルバマゼピンによる肝切除後肝再生促進機構の解析 (2012)
  • Author(s): 川口 司、小玉尚宏、巽 智秀、他
  • Organizer: 肝臓学会総会 (第48回)
  • Place of Presentation: 石川県金沢市
• [Presentation] 肝癌に対する新規アジュバント疎水化ポリγ-グルタミン酸ナノ粒子を用いたペプチドワクチン (2012)
  • Author(s): 巽 智秀、明石 満、竹原徹郎
  • Organizer: JDDW2012第20回日本消化器関連学会週間、第16回肝臓学会大会
  • Place of Presentation: 兵庫県神戸市
• [Presentation] 非癌部のFAP発現は肝癌術後再発予測因子となりうる (2012)
  • Author(s): 常松日奈子、巽 智秀、甲賀啓介、他
  • Organizer: JDDW2012第20回日本消化器関連学会週間、第54回消化器病学会大会
  • Place of Presentation: 兵庫県神戸市
• [Presentation] 肝細胞障害が誘導する酸化ストレスと肝発癌 (2012)
  • Author(s): 疋田隼人、巽 智秀、竹原徹郎
  • Organizer: JDDW2012第20回日本消化器関連学会週間、第54回消化器病学会大会
  • Place of Presentation: 兵庫県神戸市
• [Presentation] IFN治療がC型肝炎の肝メチル化に与える影響について (2012)
  • Author(s): 清水 聡、巽 智秀、重川 稔、他
  • Organizer: 癌学会総会(第71回)
  • Place of Presentation: 北海道札幌市
• [Presentation] 肝細胞アポトーシスの持続は、TNF-αを上昇させて肝発癌を誘導する (2012)
  • Author(s): 疋田隼人、小玉尚宏、巽 智秀、他
  • Organizer: 癌学会総会(第71回)
  • Place of Presentation: 北海道札幌市
• [Presentation] Oxidative stresses play a major role in cancer development in apoptosis-prone liver (2012)
  • Author(s): Hikita H, Kodama T, Tatsumi T, et al
  • Organizer: 第63回米国肝臓学会
  • Place of Presentation: 米国ボストン市
• [Presentation] NK cells might deplete liver myeloid-derived suppressor cells via targeting NK activating molecules in metastatic liver tumor-bearing mice (2012)
  • Author(s): Aono S, Tatsumi T, Aketa H, et al.
  • Organizer: 第63回米国肝臓学会
  • Place of Presentation: 米国ボストン市
• [Presentation] Carbamazepine promotes liver regeneration in hepatectomized mice through activation of mTOR pathway (2012)
  • Author(s): Kawaguchi T, Kodama T, Tatsumi T, et al.
  • Organizer: 第63回米国肝臓学会
  • Place of Presentation: 米国ボストン市
• [Presentation] The BH3-only proteins, Bim and Bid, constitutively participate in the healthy Bcl-2 rheostat regulating hepatocyte life and death via the mitochondrial pathway of apoptosis (2012)
  • Author(s): Kodama T, Hikita H, Tatsumi T, et al.
  • Organizer: 第63回米国肝臓学会
  • Place of Presentation: 米国ボストン市
• [Presentation] Interleukin-17 producing γδT cell is responsible for iNKT cell deficiency-induced liver inflammation (2012)
  • Author(s): Nishio K, Miyagi T, Tatsumi T, et al.
  • Organizer: 第63回米国肝臓学会
  • Place of Presentation: 米国ボストン市
• [Presentation] Differential roles of palmitic acid and oleic acid in regulation of apoptosis and autophagy in non-alcoholic fatty liver disease (2012)
  • Author(s): Tanaka S, Hikita H, Tatsumi T, et al.
  • Organizer: 第63回米国肝臓学会
  • Place of Presentation: 米国ボストン市
• [Presentation] Activation of Ras signaling pathway causes development and progression of hepatocellular carcinoma, the latter of which is critically dependent on STAT3 (2012)
  • Author(s): Shigekawa M, Hikita H, et al.
  • Organizer: 第63回米国肝臓学会
  • Place of Presentation: 米国ボストン市
• [Book] 肝炎診療マニュアル 「肝癌」 (2013)
  • Author(s): 巽 智秀
  • Total Pages: 31
  • Publisher: 中外医学社
• [Book] 消化器疾患治療マニュアル第2版「肝硬変」 (2013)
  • Author(s): 巽 智秀、青野悟志
  • Total Pages: 15
  • Publisher: 金芳堂
• [Book] Annual Review 消化器 2012 (2012)
  • Author(s): 巽 智秀、竹原徹郎
  • Total Pages: 5
  • Publisher: 中外医学社