Expression status of stemness-related genes in nonalcoholic steatohepatitis and clarification of the carcinogenesis mechanism

• Project/Area Number: 26461024
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Kogiso Tomomi 東京女子医科大学, 医学部, 准講師 (10318082)
• Co-Investigator(Kenkyū-buntansha): 橋本 悦子 東京女子医科大学, 医学部, 教授 (40130273) ; 山本 雅一 東京女子医科大学, 医学部, 教授 (60220498)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: steatohepatitis / stemness marker / hepatocellular carcinoma / 非アルコール性脂肪肝炎 / stemness遺伝子 / Nanog / EpCAM / 非アルコール性脂肪肝炎 (NASH) / 肝癌(HCC) / 非アルコール性脂肪肝炎（NASH）

Outline of Final Research Achievements

1)Nanog was expressed in 85% of liver tissue from patients with nonalcoholic steatohepatitis (NASH), and EpCAM was expressed in 45%. 2) A comparison of clinical parameters between patients with strongly positive/weakly positive Nanog expression revealed total-bilirubin of 0.9/0.4 mg/dL, alanine transaminase of 47/22 U/L, prothrombin time (PT) of 84/100%, and fasting blood sugar of 104/227 mg/dL with significant differences (p < 0.05). PT% was higher in the weakly positive EpCAM group (81/ 98%) than that in the strongly positive EpCAM group. 3) EpCAM expression was higher in advanced fibrosis cases. Nanog expression was higher in cases of NASH-hepatocellular carcinoma (HCC); therefore, it may be important in the initiation of HCC. 4) The iTRAQ technique, which detects protein expression, led to the detection of 4,000 candidate proteins. Each protein was evaluated for its role in HCC initiation and progression.

Research Products

• [Journal Article] The Relationship between the Growth Hormone/Insulin-like Growth Factor System and the Histological Features of Nonalcoholic Fatty Liver Disease (2017)
  • Author(s): Chishima S, Kogiso T, Matsushita N, Hashimoto E, Tokushige K.
  • Journal Title: Internal Medicine Volume: 56 Issue: 5 Pages: 473-480
  • DOI: 10.2169/internalmedicine.56.7626
  • NAID: 130005399415
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] Response to tolvaptan and its effect on prognosis in cirrhotic patients with ascites. (2016)
  • Author(s): Kogiso T, Yamamoto K, Kobayashi M, Ikarashi Y, Kodama K, Taniai M, Torii N, Hashimoto E, Tokushige K.
  • Journal Title: Hepatol Res. Volume: - Issue: 9 Pages: 835-844
  • DOI: 10.1111/hepr.12822
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Successful Treatment of Ascites using a Denver^® Peritoneovenous Shunt in a Patient with Paroxysmal Nocturnal Hemoglobinuria and Budd-Chiari syndrome (2016)
  • Author(s): Kogiso T, Hashimoto E, Ito T, Hara T, Ikarashi Y, Kodama K, Taniai M, Torii N, Yoshinaga K, Morita S, Takahashi Y, Tanaka J, Sakai S, Yamamoto M, Tokushige K.
  • Journal Title: Internal Medicine Volume: 55 Issue: 20 Pages: 2957-2963
  • DOI: 10.2169/internalmedicine.55.7087
  • NAID: 130005430009
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Safety and efficacy of long-term tolvaptan therapy for decompensated liver cirrhosis. (2016)
  • Author(s): Kogiso T, Tokushige K, Hashimoto E, Ikarashi Y, Kodama K, Taniai M, Torii N, Shiratori K.
  • Journal Title: Hepatol Res. Volume: 46 Issue: 3
  • DOI: 10.1111/hepr.12547
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical Importance of Non-alcoholic Fatty Liver Diseases. Topics: IV. Relation of NAFLD with lifestyle-related disease including obesity, dyslipidemia and hypertension. (2016)
  • Author(s): Kogiso T.
  • Journal Title: Nihon Naika Gakkai Zasshi. Volume: 105 Pages: 31-7
• [Journal Article] Four cases of type 1 diabetes mellitus showing sharp serum transaminase increases and hepatomegaly due to glycogenic hepatopathy. (2016)
  • Author(s): Ikarashi Y, Kogiso T, Hashimoto E, Yamamoto K, Kodama K, Taniai M, Torii N, Takaike H, Uchigata Y, Tokushige K.
  • Journal Title: Hepatol Res. Volume: なし Issue: 3
  • DOI: 10.1111/hepr.12713
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease and alcoholic liver disease: multicenter survey. (2016)
  • Author(s): Tokushige K, Hyogo H, Nakajima T, Ono M, Kawaguchi T, Honda K, Eguchi Y, Nozaki Y, Kawanaka M, Tanaka S, Imajo K, Sumida Y, Kamada Y, Fujii H, Suzuki Y, Kogiso T, Karino Y, Munekage K, Kuromatsu R, Oeda S, Yanase M, Mori K, Ogawa Y, Seko Y, Takehara T, Itoh Y, Nakajima A, Kanemasa K, Saibara T
  • Journal Title: J Gastroenterol Volume: 印刷中 Issue: 6 Pages: 586-96
  • DOI: 10.1007/s00535-015-1129-1
  • Peer Reviewed / Open Access
• [Journal Article] Spontaneous clearance of HCV accompanying hepatitis after liver transplantation. (2015)
  • Author(s): Kogiso T, Hashimoto E, Ikarashi Y, Kodama K, Taniai M, Torii N, Egawa H, Yamamoto M, Tokushige K.
  • Journal Title: Clin J Gastroenterol. Volume: なし Issue: 5 Pages: 323-329
  • DOI: 10.1007/s12328-015-0602-y
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mycophenolate mofetil may induce prolonged severe anemia during pegylated-interferon/ribavirin/simeprevir therapy in liver transplant recipients. (2015)
  • Author(s): Kogiso T, Tokushige K, Hashimoto E, Taniai M, Omori A, Kotera Y, Egawa H, Yamamoto M, Shiratori K.
  • Journal Title: Clin J Gastroenterol. Volume: 8 Issue: 3 Pages: 156-61
  • DOI: 10.1007/s12328-015-0570-2
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A case report: primary hyperoxaluria complicated with liver cirrhosis. (2015)
  • Author(s): 1.Kogiso T, Tokushige K, Hashimoto E, Miyakata C, Taniai M, Torii N, Omori A, Kotera Y, Egawa H, Yamamoto M, Nagata M, Shiratori K.
  • Journal Title: Hepatol Res. Volume: なし Issue: 12 Pages: 1251-5
  • DOI: 10.1111/hepr.12494
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease and alcoholic liver disease: multicenter survey. (2015)
  • Author(s): Tokushige K, Hyogo H, Nakajima T, Ono M, Kawaguchi T, Honda K, Eguchi Y, Nozaki Y, Kawanaka M, Tanaka S, Imajo K, Sumida Y, Kamada Y, Fujii H, Suzuki Y, Kogiso T, et al.
  • Journal Title: J Gastroenterol. Volume: なし
  • Peer Reviewed
• [Journal Article] Daclatasvir/Asunaprevir Therapy Provides High Tolerability and Effectiveness for HCV-Positive Kidney Transplant Recipients. (2015)
  • Author(s): Kogiso T, Hashimoto E, Yamamoto K, Ikarashi Y, Kodama K, Taniai M, Torii N, Tanabe K, Ishida H, Fuchinoue S, Tokushige K.
  • Journal Title: J Liver: Dis Transplant Volume: 4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Efficient induction of apoptosis by wee1 kinase inhibition in hepatocellular carcinoma cells. (2014)
  • Author(s): 2.Kogiso T, Nagahara H, Hashimoto E, Ariizumi S, Yamamoto M, Shiratori K.
  • Journal Title: PLoS One. Volume: 24 Issue: 6 Pages: e100495-e100495
  • DOI: 10.1371/journal.pone.0100495
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 非アルコール性脂肪肝炎 (NASH)における性差と年齢の関与; -生活習慣病、脂肪測定、アディポサイトカイン、遺伝子多型を中心に- (2014)
  • Author(s): 小木曽智美、橋本悦子、徳重克年、千嶋さやか、児玉和久、戸張真紀、松下典子、谷合麻紀子、鳥居信之、白鳥敬子.
  • Journal Title: 肝臓 Volume: 55 Pages: 199-205
  • NAID: 130004495334
  • Peer Reviewed
• [Presentation] Risk factors of primary biliary cholangitis (PBC) recurrence after liver transplantation in female patients: A Japanese multicenter retrospective study. (2016)
  • Author(s): Kogiso T, Egawa H, Hashimoto E, Tokushige K, Sakisaka S, Teramukai S, Sakabayashi S , Yamamoto M, Umeshita K , Uemoto S.
  • Organizer: The 67th annual meeting of the American Association for the Study of Liver Diseases (AASLD)
  • Place of Presentation: Boston
  • Year and Date: 2016-11-11
• [Presentation] 移植後の原発性胆汁性肝硬変再発におけるリスク因子の検討 (2016)
  • Author(s): 小木曽智美、江川裕人、徳重克年.
  • Organizer: 第24回日本消化器関連学会週間 (JDDW)
  • Place of Presentation: 神戸
  • Year and Date: 2016-11-03
• [Presentation] 肝・腎移植後のC型肝炎治療経過の検討 (2016)
  • Author(s): 小木曽智美、五十嵐悠一、児玉和久、谷合麻紀子、鳥居信之、橋本悦子、徳重克年、江川裕人、山本雅一
  • Organizer: 第34回日本肝移植研究会
  • Place of Presentation: 旭川
  • Year and Date: 2016-07-07
• [Presentation] NASH発症・進展に関する遺伝的バックグランドの検討 (2016)
  • Author(s): 小木曽智美、橋本悦子、徳重克年.
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: 千葉
  • Year and Date: 2016-05-19
• [Presentation] 腎移植後C型肝炎ウイルスに対するインターフェロンフリー治療の有効性と安全性の検討 (2016)
  • Author(s): 小木曽智美、橋本悦子、五十嵐悠一、児玉和久、谷合麻紀子、鳥居信之、徳重克年
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 東京
  • Year and Date: 2016-04-21
• [Presentation] An efficacy and safety of daclatasvir/asunaprevir therapy for HCV-positive kidney transplantation. (2016)
  • Author(s): Kogiso T, Hashimoto E, Kuniko Y, Ikarashi Y, Kodama K, Torii N, Taniai M, Tokushige K.
  • Organizer: The 25th annual meeting of the Asian Pacific Association for the Study of the Liver (APASL)
  • Place of Presentation: Tokyo International Convention Center Pamir
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] Risk factors for hepatocellular carcinoma recurrence in patients with nonalcoholic and alcoholic fatty liver diseases: A Japanese multicenter survey (2015)
  • Author(s): Kogiso T, Hashimoto E, Hyogo H, Nakajima T, Ono M, Kawaguchi T, Honda K, Eguchi Y, Nozaki Y, Kawanaka M, Imajo K, Sumida Y, Kamada Y, Fujii H, Suzuki Y, and Tokushige K
  • Organizer: The 66th annual meeting of the American Association for the Study of Liver Diseases (AASLD),
  • Place of Presentation: San Francisco, U.S.A., Moscone West Convention Center
  • Year and Date: 2015-11-13
  • Int'l Joint Research
• [Presentation] (International Session1 Pathological features of nonalcoholic steatohepatitis(JSH/JSGE))The hostological course of nonalcoholic steatohepatitis:a longitudinal study of sequential liver biopsies (2015)
  • Author(s): Kogiso T, Hashimoto E, Tokushige K.
  • Organizer: The19th General Meeting of the Japan Society of Hepatology/57th Annual Meeting of the Japanese Society of Gastroenterology (JDDW2015)
  • Place of Presentation: 東京 グランドプリンスホテル新高輪・国際館パミール・グランドプリンスホテル高輪
  • Year and Date: 2015-10-08
  • Int'l Joint Research
• [Presentation] NAFLD及びアルコール性肝障害を基盤にした肝細胞癌の他施設研究ー性差に関してー (2015)
  • Author(s): 小木曽智美, 五十嵐悠一, 谷合麻紀子, 鳥居信之, 橋本悦子, 徳重克年
  • Organizer: 第11回消化器病における性差医学・医療研究会
  • Place of Presentation: 旭川 旭川グランドホテル
  • Year and Date: 2015-07-25
• [Presentation] （パネルディスカッション3 ウイルス肝炎に対する肝移植ー抗ウイルス療法の変遷と術後管理）肝移植後C型肝炎ウイルスの最新治療薬と免疫抑制剤との薬物相互作用 (2015)
  • Author(s): 小木曽智美,橋本悦子,徳重克年
  • Organizer: 第33回日本肝移植研究会
  • Place of Presentation: 神戸 ホテルオークラ神戸
  • Year and Date: 2015-05-28
• [Presentation] 肝硬変に伴う腹水に対するトルバプタン治療の長期経過の検討 (2015)
  • Author(s): 小木曽智美,徳重克年、橋本悦子、児玉和久、戸張真紀、谷合麻紀子、鳥居信之、白鳥敬子
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本 ホテル日航熊本など
  • Year and Date: 2015-05-21
• [Presentation] 移植後のC型肝炎ウイルス再感染の経過 (2015)
  • Author(s): 小木曽智美, 徳重克年, 橋本悦子, 五十嵐悠一, 児玉和久, 谷合麻紀子, 鳥居信之, 白鳥敬子, 江川裕人, 山本雅一
  • Organizer: 第101回日本消化器病学会総会
  • Place of Presentation: 仙台 仙台国際センター
  • Year and Date: 2015-04-23
• [Presentation] Resistance to TGF-beta-induced apoptosis is not associated with the de-differentiation in hepatocellular carcinoma. (2015)
  • Author(s): Kogiso T, Hashimoto E, Kodama K, Ikarashi Y, Torii N, Taniai M, Tokushige K, Shiratori K.
  • Organizer: American Association for Cancer Research (AACR) 106th Annual Meeting 2015
  • Place of Presentation: Philadelphia, U.S.A., Pennsylvania Convention Center
  • Year and Date: 2015-04-18
  • Int'l Joint Research
• [Presentation] 成人急性肝不全に対する生体部分肝移植の検討 (2014)
  • Author(s): 小木曽智美、徳重克年、橋本悦子.
  • Organizer: 第40回日本肝臓学会東部会
  • Place of Presentation: 京王プラザホテル (東京都新宿区)
  • Year and Date: 2014-11-27 – 2014-11-28
• [Presentation] Cancer stem cell marker expression and their clinicopathological features in NASH patients with hepatocellular carcinoma. (2014)
  • Author(s): Kogiso T, Taniai M, Hashimoto E.
  • Organizer: The 25th Annual Meeting of the Japanese Society for Gastroenterological Carcinogenesis.
  • Place of Presentation: ホテル日航福岡 (福岡県福岡市)
  • Year and Date: 2014-11-13 – 2014-11-14
• [Presentation] 肝硬変による難治性腹水に対するトルバプタンの有効性およびその効果予測因子に関する検討 (2014)
  • Author(s): 小木曽智美、徳重克年、橋本悦子.
  • Organizer: 第18回日本肝臓学会大会、第56回日本消化器病学会大会
  • Place of Presentation: 神戸国際展示場・会議場・ポートピアホテル (兵庫県神戸市)
  • Year and Date: 2014-10-23 – 2014-10-26
• [Presentation] 肝移植後、自然経過でC型肝炎ウイルス消失を来した2症例 (2014)
  • Author(s): 小木曽智美、徳重克年、橋本悦子、谷合麻紀子、鳥居信之、児玉和久、白鳥敬子、江川裕人、山本雅一.
  • Organizer: 第32回日本肝移植研究会
  • Place of Presentation: 京王プラザホテル (東京都新宿区)
  • Year and Date: 2014-07-03 – 2014-07-04
• [Presentation] Early Morning Breakfast Workshop 「Carcinogenesis, Genomics, Pathways and Targets」 Molecular mechanisms underlying the development of hepatocellular carcinoma (HCC) (2014)
  • Author(s): Kogiso T, Hashimoto E.
  • Organizer: 第4回国際肝癌シンポジウムKYOTO (4th International Kyoto Liver Cancer Symposium (IKLS) )
  • Place of Presentation: 国立京都国際会館 (京都府京都市)
  • Year and Date: 2014-06-07 – 2014-06-08
  • Invited
• [Presentation] 幹細胞マーカー発現から見た非アルコール性脂肪性肝炎の病態の臨床病理学的検討 (2014)
  • Author(s): 小木曽智美、谷合麻紀子、橋本悦子.
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ (東京都千代田区)
  • Year and Date: 2014-05-29 – 2014-05-30
• [Presentation] 当院における成人急性肝不全に対する生体部分肝移植の検討 (2014)
  • Author(s): 小木曽智美、徳重克年、橋本悦子、児玉和久、戸張真紀、谷合麻紀子、鳥居信之、白鳥敬子、江川裕人、山本雅一.
  • Organizer: 第100回日本消化器病学会総会
  • Place of Presentation: 東京国際フォーラム (東京都千代田区)
  • Year and Date: 2014-04-23 – 2014-04-26
• [Presentation] Differential expression of cancer stem cell markers and their clinicopathological features in hepatocellular carcinoma patients with different etiologies. (2014)
  • Author(s): Kogiso T, Hashimoto E, Kodama K, Tobari M, Matsushita N, Torii N, Taniai M, Tokushige K, Shiratori K.
  • Organizer: American Association for Cancer Research (AACR)
  • Place of Presentation: San Diego, U.S.A.
  • Year and Date: 2014-04-05 – 2014-04-09
• [Book] Annual Review 2016 消化器 (2016)
  • Author(s): 小木曽智美、徳重克年
  • Total Pages: 247
  • Publisher: 中外医学社
• [Book] 日本内科学会雑誌第105巻第1号 (2016)
  • Author(s): 小木曽智美
  • Total Pages: 174
  • Publisher: 一般社団法人 日本内科学会
• [Book] Fluid management renaissance (2014)
  • Author(s): 小木曽智美、徳重克年、橋本悦子.
  • Publisher: メディカルレビュー社
• [Book] PBCの診断 第4巻『難治性肝疾患の診療を極める』 (2014)
  • Author(s): 小木曽智美、谷合麻紀子、橋本悦子.
  • Publisher: 文光堂