The role of FoxM1 transcription factor in the development of hepatic inflammation, liver fibrosis, and hepatocellular carcinoma: the study using conditional transgenic mice

• Project/Area Number: 26461001
• 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: YOSHIDA YUICHI 大阪大学, 医学系研究科, 特任助教 (30457014)
• Co-Investigator(Kenkyū-buntansha): 木曽 真一 大阪大学, 医学系研究科, 特任准教授 (40335352)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: FoxM1 / 肝細胞癌 / 肝細胞死 / 炎症 / トランスジェニックマウス / 肝癌 / 肝内炎症 / 肝線維化 / HCC / NAFLD / 脂肪肝

Outline of Final Research Achievements

Forkhead Box M1 (FoxM1) is a transcription factor that regulates cell cycle and plays regeneration and plays an important role in the development of hepatocellular carcinoma. To elucidate the functional role of FoxM1 in hepatocytes, we developed a novel transgenic mice in which we can regulate expression of human FoxM1 in murine hepatocytes under the control of tetracycline. Unexpectedly, transgenic expression of FoxM1 in hepatocytes resulted in hepatocyte apoptosis and hepatic inflammation. Finally, these transgenic mice spontaneously developed marked liver fibrosis. These data reveled a new function of FoxM1 in hepatocyte death, hepatic inflammation, and subsequent liver fibrosis.

Research Products

• [Journal Article] Increased expression of Forkhead box M1 transcription factor is associated with clinicopathological features and confers a poor prognosis in human hepatocellular carcinoma (2017)
  • Author(s): Egawa M, Yoshida Y, Ogura S, Kurahashi T, Kizu T, Furuta K, Kamada Y, Chatani N, Hamano M, Kiso S, Hikita H, Tatsumi T, Eguchi H, Nagano H, Doki Y, Mori M, Takehara T
  • Journal Title: Hepatology Research Volume: 印刷中 Pages: 1196-1205
  • DOI: 10.1111/hepr.12854
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ultra-deep sequencing analysis of resistance-associated variants during retreatment with simeprevir-based triple therapy after failure of telaprevir-based triple therapy in patients with genotype 1 hepatitis C virus infection. (2017)
  • Author(s): Morishita N, Hiramatsu N, Oze T, Urabe A, Tahata Y, Yamada R, Yakushijin T, Hosui A, Iio S, Yamada A, Hagiwara H, Mita E, Yamada Y, Ito T, Inada M, Katayama K, Yabuuchi I, Imai Y, Hikita H, Sakamori R, Yoshida Y, Tatsumi T, Hayashi N, Takehara T.
  • Journal Title: Hepatol Res. Volume: 印刷中
  • DOI: 10.1111/hepr.12817
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hepatic aberrant glycosylation by N-acetylglucosaminyltransferase V accelerates HDL assembly. (2016)
  • Author(s): Kamada Y, Kida S, Hirano KI, Yamaguchi S, Suzuki A, Hashimoto C, Kimura A, Sato M, Fujii H, Sobajima T, Yamamoto A, Ebisutani Y, Takamatsu S, Shinzaki S, Yoshida Y, Yamada M, Nagasaka H, Takehara T, Miyoshi E.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: 311
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen-induced liver injury in mice. (2016)
  • Author(s): Furuta K, Yoshida Y, Ogura S, Kurahashi T, Kizu T, Maeda S, Egawa M, Chatani N, Nishida K, Nakaoka Y, Kiso S, Kamada Y, Takehara T.
  • Journal Title: Hepatology. Volume: 63 Pages: 1340-1355
  • DOI: 10.1002/hep.28410
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The impact of an inosine triphosphate pyrophosphatase genotype on bilirubin increase in chronic hepatitis C patients treated with simeprevir, pegylated interferon plus ribavirin. (2016)
  • Author(s): Tahata Y, Hiramatsu N, Oze T, Morishita N, Harada N, Yamada R, Yakushijin T, Mita E, Hagiwara H, Yamada Y, Ito T, Hijioka T, Inada M, Katayama K, Tamura S, Yoshihara H, Inoue A, Imai Y, Irishio K, Kato M, Hikita H, Sakamori R, Miyagi T, Yoshida Y, Tatsumi T, Hamasaki T, Hayashi N, Takehara T
  • Journal Title: J Gastroenterol. Volume: 51 Pages: 252-259
  • DOI: 10.1007/s00535-015-1105-9
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ectopic expression of N-acetylglucosaminyl transferase V (GnT-V) accelerates hepatic triglyceride synthesis. (2016)
  • Author(s): Kamada Y, Ebisutani Y, Kida S, Mizutani K, Akita M, Yamamoto A, Fujii H, Sobajima T, Terao N, Takamatsu S, Yoshida Y, Takehara T, Miyoshi E
  • Journal Title: Hepatol Res Volume: 46 Pages: 1189-129
  • DOI: 10.1111/hepr.12541
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A novel noninvasive diagnostic method for nonalcoholic steatohepatitis using two glycobiomarkers． (2015)
  • Author(s): Kamada Y, Ono M, Hyogo H, Fujii H, Sumida Y, Mori K, Tanaka S, Yamada M, Akita M, Mizutani K, Fujii H, Yamamoto A, Takamatsu S, Yoshida Y, Itoh Y, Kawada N, Chayama K, Saibara T, Takehara T, Miyoshi E
  • Journal Title: Hepatology Volume: 62 Pages: 1433-1443
  • DOI: 10.1002/hep.28002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fetuin-A negatively correlates with liver and vascular fibrosis in nonalcoholic fatty liver disease subjects. (2015)
  • Author(s): Kamada Y*, Sato M* (equally contributed), Takeda Y, Kida S, Ohara Y, Fujii H, Akita M, Mizutani K, Yoshida Y, Yamada M, Hougaku H, Takehara T, Miyoshi E.
  • Journal Title: Liver Int. Volume: 35 Pages: 925-35
  • DOI: 10.1111/liv.12478
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice. (2015)
  • Author(s): Kizu T, Yoshida Y, Furuta K, Ogura S, Egawa M, Chatani N, Hamano M, Takemura T, Ezaki H, Kamada Y, Nishida K, Nakaoka Y, Kiso S, Takehara T
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: 308
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] N-acetylglucosaminyltransferase V exacerbates concanavalin A-induced hepatitis in mice. (2015)
  • Author(s): Kamada Y, Sato M, Kida S, Akita M, Mizutani K, Fujii H, Sobajima T, Yoshida Y, Shinzaki S, Takamatsu S, Takehara T, Miyoshi E.
  • Journal Title: Mol Med Rep Volume: 5 Pages: 3573-3584
  • DOI: 10.3892/mmr.2015.3168
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice (2015)
  • Author(s): Kizu T, Yoshida Y, Furuta K, Ogura S, Egawa M, Chatani N, Hamano M, Takemura T, Ezaki H, Kamada Y, Nishida K, Nakaoka Y, Kiso S, Takehara T.
  • Journal Title: American journal of physiology.Gastrointestinal and liver physiology. Volume: 308 Pages: 613-624
  • DOI: 10.1152/ajpgi.00289.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The real impact of telaprevir dosage on the antiviral and side effects of telaprevir, pegylated interferon and ribavirin therapy for chronic hepatitis C patients with HCV genotype 1. (2015)
  • Author(s): Oze T, Hiramatsu N, Yoshida Y et al.
  • Journal Title: J Viral Hepat Volume: 22 Pages: 254-262
  • DOI: 10.1111/jvh.12289
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The prospective randomized study on telaprevir at 1500 or 2250 mg with pegylated interferon plus ribavirin in Japanese patients with HCV genotype 1. (2015)
  • Author(s): Oze T, Hiramatsu N, Yoshida Y et al.
  • Journal Title: J Gastroenterol Volume: 50 Pages: 313-22
  • DOI: 10.1007/s00535-014-0965-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Significance of liver stiffness measurement by acoustic radiation force impulse (ARFI) among hepatitis C patients. (2014)
  • Author(s): Yamada R, Hiramatsu N, Oze T, Morishita N, Harada N, Miyazaki M, Yakushijin T, Miyagi T, Yoshida Y, Tatsumi T, Kanto T, Hayashi N, Takehara T.
  • Journal Title: J Med Virol Volume: 86 Pages: 241-247
  • DOI: 10.1002/jmv.23840
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Post-treatment levels of α-fetoprotein predict incidence of hepatocellular carcinoma after nterferon therapy. (2014)
  • 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) Pages: 1186-1195
  • DOI: 10.1016/j.cgh.2013.11.033
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Liver stiffness measurement by acoustic radiation force impulse is useful in predicting the presence of esophageal varices or high-risk esophageal varices among patients with HCV-related cirrhosis. (2014)
  • Author(s): Morishita N, Hiramatsu N, Yoshida Y et al.
  • Journal Title: J Gastroenterol Volume: 49 Pages: 1175-1182
  • DOI: 10.1007/s00535-013-0877-z
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] FoxM1転写因子による慢性肝疾患の制御機構：新規マウスモデルを用いた検討 (2016)
  • Author(s): 倉橋知英、吉田雄一、小倉智志、柄川真弓、古田訓丸、鎌田佳宏、木曽真一、疋田隼人、巽智秀、竹原徹郎
  • Organizer: 第41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: 2016-12-08
• [Presentation] FoxM1転写因子を介した癌脂質代謝プログラムに基づく新たな肝癌治療戦略 (2016)
  • Author(s): 小倉智志、吉田雄一、倉橋知英、柄川真弓、古田訓丸、木曽真一、鎌田佳宏、疋田隼人、 巽智秀、竹原徹郎
  • Organizer: 第41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: 2016-12-08
• [Presentation] Metabolic regulation of FoxM1 transcription factor by mevalonate-Rho pathways in human hepatocarcinoma. (2016)
  • Author(s): Satoshi Ogura, Yuichi Yoshida, Tomohide Kurahashi, Mayumi Egawa, Kunimaro Furuta, Shinichi Kiso, Yoshihiro Kamada, Hayato Hikita, Tomohide Tatsumi and Tetsuo Takehara.
  • Organizer: The Liver Meeting 2016 - AASLD
  • Place of Presentation: HYNES CONVENTION CENTER, BOSTON, MA, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Hepatic overexpression of oncogenic FoxM1 transcription factor promotes hepatocyte death and hepatic inflammation in mice. (2016)
  • Author(s): Tomohide Kurahashi, Yuichi Yoshida, Satoshi Ogura, Mayumi Egawa, Kunimaro Furuta, Yoshihiro Kamada, Shinichi Kiso, Hayato Hikita, Tomohide Tatsumi, Tetsuo Takehara.
  • Organizer: The Liver Meeting 2016 - AASLD
  • Place of Presentation: HYNES CONVENTION CENTER, BOSTON, MA, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] 肝癌における癌脂質代謝経路の意義とFoxM1の関与について (2016)
  • Author(s): 小倉智志、吉田雄一、竹原徹郎
  • Organizer: 第24回 日本消化器関連学会週間
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市中央区）
  • Year and Date: 2016-11-03
• [Presentation] 癌脂質代謝からみた肝癌制御の可能性：Rho/YAP/FoxM1 経路の意義 (2016)
  • Author(s): 小倉智志、吉田雄一、竹原徹郎
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張（千葉県千葉市美浜区）
  • Year and Date: 2016-05-19
• [Presentation] 急性肝不全病態においてGab1 は肝細胞運命の決定を担う (2016)
  • Author(s): 古田訓丸, 吉田雄一, 倉橋知英, 小倉智志, 柄川真弓, 木曽真一, 鎌田佳宏, 竹原徹郎
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張（千葉県千葉市美浜区）
  • Year and Date: 2016-05-19
• [Presentation] FoxM1 転写因子を介した新たな肝癌脂質代謝制御：治療標的としての可能性について (2016)
  • Author(s): 小倉智志、吉田雄一、柄川真弓、倉橋 知英、古田訓丸、木曽真一、鎌田佳宏、竹原徹郎
  • Organizer: 第102回 日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-04-21
• [Presentation] 肝癌脂質代謝におけるFoxM1転写因子を介したシグナル経路の意義 (2015)
  • Author(s): 小倉智志、吉田雄一、竹原徹郎
  • Organizer: 第41回日本肝臓学会西部会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-12-03
• [Presentation] Gab1 adaptor protein is an essential gatekeeper to balance hepatocyte death and proliferation during acetaminophen-induced liver injury in mice (2015)
  • Author(s): Yuichi Yoshida, Kunimaro Furuta, Satoshi Ogura, Tomohide Kurahashi, Mayumi Egawa, Shinichi Kiso, Yoshihiro Kamada, and Tetsuo Takehara
  • Organizer: 第66回米国肝臓学会議
  • Place of Presentation: Moscone Convention Center, San Francisco, USA
  • Year and Date: 2015-11-17
  • Int'l Joint Research
• [Presentation] A novel noninvasive diagnostic method for nonalcoholic steatohepatitis (NASH) using two glycobiomarkers (2015)
  • Author(s): Yoshihiro Kamada, Masafumi Ono, Hideyuki Hyogo, Hideki Fujii, Yoshio Sumida, Kohjiroh Mori, Saiyu Tanaka, Makoto Yamada, Maaya Akita, Kayo Mizutani, Hironobu Fujii, Akiko Yamamoto, Shinji Takamatsu, Yuichi Yoshida, Yoshito Itoh, Norifumi Kawada, Kazuaki Chayama, Toshiji Saibara, Tetsuo Takehara, Eiji Miyoshi
  • Organizer: 第66回米国肝臓学会議
  • Place of Presentation: Moscone Convention Center, San Francisco, USA
  • Year and Date: 2015-11-17
  • Int'l Joint Research
• [Presentation] 肝細胞癌におけるHMG-CoA還元酵素阻害剤によるFoxM1転写因子の発現制御 (2015)
  • Author(s): 小倉智志、吉田雄一、柄川真弓、古田訓丸、木津 崇、木曽真一、鎌田佳宏、竹原徹郎
  • Organizer: 第23回JDDW
  • Place of Presentation: グランドプリンスホテル新高輪
  • Year and Date: 2015-10-08
• [Presentation] 肝細胞癌におけるメバロン酸経路を介したFoxM1転写因子の制御と臨床応用の可能性について (2015)
  • Author(s): 小倉智志、吉田雄一、柄川真弓、古田訓丸、木津 崇、木曽真一、鎌田佳宏、竹原徹郎
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本
  • Year and Date: 2015-05-22
• [Presentation] 重症肝不全病態における ストレス応答制御分子としての 肝細胞 Gab1 の意義と治療標的としての可能性 (2015)
  • Author(s): 古田訓丸, 吉田雄一, 木津崇, 小倉智志, 柄川真弓, 茶谷徳啓, 鎌田佳宏, 木曽真一, 竹原徹郎
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本
  • Year and Date: 2015-05-21
• [Presentation] Loss of Grb2-associated binder 1 results in enhanced hepatocyte necrosis and high mortality in mice with acute liver failure (2014)
  • Author(s): Kunimaro Furuta, Yuichi Yoshida, Takashi Kizu, Satoshi Ogura, Mayumi Egawa, Norihiro Chatani, Yoshihiro Kamada, Shinichi Kiso, Tetsuo Takehara
  • Organizer: 65th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: John B. Hynes Veterans Memorial Convention Center, Boston, MA, USA
  • Year and Date: 2014-11-09
• [Presentation] Grb2-associated binder 1 protects against liver fibrosis via suppression of CCL5 production from hepatocytes (2014)
  • Author(s): Yuichi Yoshida, Takashi Kizu, Kunimaro Furuta, Satoshi Ogura, Mayumi Egawa, Norihiro Chatani, Yoshihiro Kamada, Shinichi Kiso, Tetsuo Takehara
  • Organizer: 65th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: John B. Hynes Veterans Memorial Convention Center, Boston, MA, USA
  • Year and Date: 2014-11-09
• [Presentation] 急性肝不全におけるアダプター蛋白質Gab1を介した恒常性維持と治療標的としての可能性について (2014)
  • Author(s): 古田訓丸、吉田雄一、竹原徹郎
  • Organizer: 第18回日本肝臓学会大会
  • Place of Presentation: 神戸国際会議場（神戸）
  • Year and Date: 2014-10-23
• [Presentation] 肝細胞壊死を起点とした再生／恒常性維持の“鍵分子”としてのGab１の意義 (2014)
  • Author(s): 吉田雄一, 古田訓丸, 竹原徹郎
  • 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）
  • Year and Date: 2014-05-29
• [Presentation] 肝線維化に対する新規治療標的としての肝細胞Gab１‐CCL５経路の意義 (2014)
  • Author(s): 吉田雄一, 木津崇, 古田訓丸, 小倉智志, 柄川真弓, 茶谷徳啓, 江崎久男, 鎌田佳宏, 木曽真一, 竹原徹郎
  • 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）
  • Year and Date: 2014-05-29