Development of YAP-dependent hepatic tumor formation and analysis of global expression of related microRNAs

• Project/Area Number: 24659030
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NISHINA Hiroshi 東京医科歯科大学, 難治疾患研究所, 教授 (60212122)
• Project Period (FY): 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2012: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: YAP / 肝癌 / 細胞競合 / アポトーシス / cDNA / マイクロRNA / HTVi法 / 網羅的遺伝子解析 / 肝がん

Research Abstract

Recently, YAP was shown to play an important role in organ size control and to be inhibited by the Hippo signaling pathway. Either transgenic overexpression of YAP or knockout of Hippo pathway genes in mouse liver results in enlargement of this organ and the eventual development of hepatic tumors. In this study, we used the method of hydrodynamic tail vein injection (HTVi) that is specific for gene transfer into liver. As a results, we succeeded in establishing an efficient system of liver cancer induction due to gain of function of the active YAP. Secondly, we analyzed the gene expression by cDNA microarray and identified more than 20 genes whose expression is increased by active YAP. Thus, our results could contribute to elucidate the mechanismof human liver cancer.

Research Products

• [Journal Article] A novel acetylation cycle of the transcription co-activator Yes-associated protein that is downstream of the Hippo pathway is triggered in response to SN2 alkylating agents (2012)
  • Author(s): Shoji Hata, Jun Hirayama, Hiroaki Kajiho, Kentaro Nakagawa, Yutaka Hata, Toshiaki Katada, Makoto Furutani-Seiki and Hiroshi Nishina
  • Journal Title: J. Biol. Chem Volume: 287 Pages: 22089-22098
• [Journal Article] Involvement of the Stress Kinase Mitogen-activated Protein Kinase Kinase 7 in the Regulation of the Mammalian Circadian Clock (2012)
  • Author(s): Yoshimi Uchida, Tomomi Osaki, Tokiwa Yamasaki, Tadanori Shimomura, Shoji Hata, Kazumasa Horikawa, Shigenobu Shibata, Takeshi Todo, Jun Hirayama and Hiroshi Nishina
  • Journal Title: J. Biol. Chem Volume: 287 Pages: 8318-8326
• [Journal Article] Light, reactive oxygen species, and magnetic fields activate ERK/MAPK signaling pathway in cultured zebrafish cells (2012)
  • Author(s): Yoshimi Uchida, Tadanori Shimomura, Jun Hirayama and Hiroshi Nishina
  • Journal Title: Appl. Magn.Reson Volume: 42 Pages: 69-77
• [Journal Article] Cancer Susceptibility andembryonic lethality in Mob1A/1Bdouble mutant mice (2012)
  • Author(s): Miki Nishio, Koichi Hamada, Kohichi Kawahara, Masato Sasaki, Fumihito Noguchi, Shuhei Chiba, Kensaku Mizuno, Satoshi O. Suzuki, Youyi Dong, Masaaki Tokuda, Takumi Morikawa, Hiroki Hikasa, Jonathan Eggenschwiler, Norikazu Yabuta, Hiroshi Nojima, Kentaro Nakagawa, Yutaka Hata, Hiroshi Nishina, Koshi Mimori, Masaki Mori, Takehiko Sasaki, Tak W. Mak, Toru Nakano, Satoshi Itami, and Akira Suzuki
  • Journal Title: J. Clin. Invest Volume: 122(12) Pages: 4505-4518
• [Journal Article] Establishment of Functioning Human Corneal Endothelial Cell Line with High Growth Potential (2012)
  • Author(s): Tadashi Yokoi, Yuko Seko, Tae Yokoi, Hatsune Makino, Shin Hatou, Masakazu Yamada, Tohru Kiyono, Akihiro Umezawa, Hiroshi Nishina, Noriyuki Azuma
  • Journal Title: PLoS ONE Volume: 7(1)
• [Journal Article] Prospective isolation and characterization of bipotent progenitor cells in early mouse liver development (2012)
  • Author(s): Ken Okada, Akihide Kamiya,Keiichi Ito, Ayaka Yanagida, Hidenori Ito, Hiroki Kondou, Hiroshi Nishina and Hiromitsu Nakauchi
  • Journal Title: Stem Cells and Development Volume: 21 Pages: 1124-1133
• [Journal Article] Splenectomy enhances the anti-fibrotic effect of bone marrow cell infusion and improves liver function in cirrhotic mice and patients (2012)
  • Author(s): Takuya Iwamoto, Shuji Terai, Yuko Mizunaga, Naoki Yamamoto, Kaoru Omori, Koichi Uchida, Takahiro Yamasaki, Yasuhiko Fujii, Hiroshi Nishina, and Isao Sakaida
  • Journal Title: J. Gastroenterol Volume: 47 Pages: 300-312
  • NAID: 10030560153
• [Journal Article] Ezetimibe reduces fatty acid quantity in liver and decreased inflammatory cell infiltration and improved NASH in medaka model (2012)
  • Author(s): Toshiyuki Oishi, Shuji Terai, Shinya Kuwashiro, Koichi Fujisawa, Toshihiko Matsumoto, Hiroshi Nishina and Isao Sakaida
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 422 Pages: 22-27
• [Journal Article] [Letters to the Editor] Reply to Sun et al.: Targeting YAP acetylation in cancer (2012)
  • Author(s): Shoji Hata and Hiroshi Nishina
  • Journal Title: J. Biol. Chem Volume: 287 Pages: 35443-35443
• [Journal Article] Diverse roles of JNK and MKK pathways in the brain (2012)
  • Author(s): Tokiwa Yamasaki, Hiroshi Kawasaki and Hiroshi Nishina
  • Journal Title: J. Signal Trans Pages: 459265-459265
• [Journal Article] [commentary] hDlk-1: A cell surface marker common to normal hepatic stem/progenitor cells and carcinomas (2012)
  • Author(s): Hiroshi Nishina
  • Journal Title: J. Biochem Volume: 152 Pages: 121-123
• [Journal Article] 活性酸素シグナルと概日リズム (2012)
  • Author(s): 平山順、仁科博史
  • Journal Title: 実験医学2012年11月増刊号 Pages: 36-41
• [Journal Article] モデル生物を用いた肝発生および肝サイズ制御機構の解明 (2012)
  • Author(s): 宮村憲央、仁科博史
  • Journal Title: 肝胆膵 Volume: 65 Pages: 21-28
• [Journal Article] 質量顕微鏡法を用いたマウス再生肝の解析 (2012)
  • Author(s): 宮村憲央、瀬藤光利、仁科博史
  • Journal Title: 生化学 Volume: 84 Pages: 680-684
  • NAID: 10031059065
• [Journal Article] A novel acetylation cycle of transcription co-activator Yes-associated protein that is downstream of Hippo pathway is triggered in response to SN2 alkylating agents. (2012)
  • Author(s): Hata S.
  • Journal Title: Journal of Biological Chemistry Volume: 287 Issue: 26 Pages: 22089-22098
  • DOI: 10.1074/jbc.m111.334714
  • Peer Reviewed
• [Journal Article] Involvement of the stress kinase mitogen-activated protein kinase kinase 7 in the regulation of the mammalian circadian clock (2012)
  • Author(s): Yoshimi Uchida, et.al.
  • Journal Title: Journal of Biological Chemistry Volume: 287 Issue: 11 Pages: 8318-8326
  • DOI: 10.1074/jbc.m111.308908
  • Peer Reviewed
• [Journal Article] Cancer susceptibility and embryonic lethality in Mobla/lb double-mutant mice. (2012)
  • Author(s): Nishio M.
  • Journal Title: J Clin Invest. Volume: 122 Issue: 12 Pages: 4505-4518
  • DOI: 10.1172/jci63735
  • Peer Reviewed
• [Journal Article] hDlk-1: A cell surface marker common to normal hepatic stem/progenitor cells and carcinomas (2012)
  • Author(s): Hiroshi Nishina
  • Journal Title: J. Biochem. Volume: 152 Issue: 2 Pages: 121-123
  • DOI: 10.1093/jb/mvs069
  • NAID: 10031166120
  • Peer Reviewed
• [Journal Article] Prospective isolation and characterization of bi-potent progenitor cells in early mouse liver development (2011)
  • Author(s): Okada K, Kamiya A, Ito K, Yanagida A, Ito H, Kondou H, Nishina H, Nakauchi H
  • Journal Title: Cells Dev Volume: (Epub ahead of print) Issue: 7 Pages: 1124-33
  • DOI: 10.1089/scd.2011.0229
  • Peer Reviewed
• [Presentation] Analyses of physiological functions of stress kinase MKK7 in developing cortex and adult nervous system (2012)
  • Author(s): Tokiwa Yamasaki
  • Organizer: Yale CNNR seminar
  • Place of Presentation: New Haven, USA
• [Presentation] A novel acetylation cycle of the transcription co-activator Yes-associated protein that is downstream of the Hippo pathway is triggered in response to SN2 alkylatingagents (2012)
  • Author(s): Hiroshi Nishina
  • Organizer: 2012 FASEB Science ResearchConference
  • Place of Presentation: Aspen, USA
• [Presentation] Stress-activated protein kinase MKK7 regulatesaxon elongation in the developing cerebral cortex (2012)
  • Author(s): Tokiwa Yamasaki
  • Organizer: Neuroscience 2012, SfN's 42nd annual meeting
  • Place of Presentation: New Orleans, USA
• [Presentation] A novel acetylation cycle of the transcription co-activator Yes-associated protein that is downstream of the Hippo pathway is triggered in response to SN2alkylating agents (2012)
  • Author(s): Shoji Hata and Hiroshi Nishina
  • Organizer: InternationalSymposium on GENETIC AND EPIGENETIC CONTROL OF CELL FATE
  • Place of Presentation: Kyoto, Japan
• [Presentation] Liver Formation and Disease: Lessons from Fish and Mouse (2012)
  • Author(s): Hiroshi Nishina
  • Organizer: 4th World Congress of Pediatric Gastroentrology, Hepatology and Nutrition
  • Place of Presentation: Taipei, Taiwan
• [Presentation] Liver development , regeneration and disease: lessons from mice and fish (2012)
  • Author(s): 仁科博史
  • Organizer: 第9回心血管幹細胞研究会
  • Place of Presentation: 東京
• [Presentation] Liver development , regeneration and disease: lessons from mice and fish (2012)
  • Author(s): 仁科博史
  • Organizer: 東京大学薬学セミナー
  • Place of Presentation: 東京
• [Presentation] モデル生物を用いた器官形成機構の解明 (2012)
  • Author(s): 仁科博史
  • Organizer: 山口大学医学部セミナー
  • Place of Presentation: 宇部
• [Presentation] 神経組織特異的Mkk7欠損マウスの解析 (2012)
  • Author(s): 岩月麻美子他
  • Organizer: 第132回日本薬学会
  • Place of Presentation: 札幌
• [Presentation] がん遺伝子産物YAPの新規翻訳後修飾アセチル化の同定 (2012)
  • Author(s): 畠星治
  • Organizer: 第16回日本肝臓医生物学研究会
  • Place of Presentation: 熱海
• [Presentation] がん遺伝子YAPによる肝細胞がんの発症機構の解明 (2012)
  • Author(s): 宮村憲央
  • Organizer: 第16回日本肝臓医生物学研究会
  • Place of Presentation: 熱海
• [Presentation] 質量顕微鏡法 (2012)
  • Author(s): 仁科博史
  • Organizer: 第55回日本腎臓学会学術総会
  • Place of Presentation: 横浜
• [Presentation] がん遺伝子産物YAPの新規翻訳後修飾アセチル化の同定 (2012)
  • Author(s): 畠星治他
  • Organizer: 第19回肝細胞研究会
  • Place of Presentation: 札幌
• [Presentation] がん遺伝子産物YAPによる細胞競合および肝がん誘導系の確立 (2012)
  • Author(s): 宮村憲央他
  • Organizer: 第19回肝細胞研究会
  • Place of Presentation: 札幌
• [Presentation] ストレス応答性キナーゼMKK7による概日リズム制御機構の解明 (2012)
  • Author(s): 内田好海他
  • Organizer: 第11回生命科学研究会
  • Place of Presentation: 秋田
• [Presentation] ストレス応答性MAPキナーゼシグナル伝達系のゼブラフィッシュ初期胚における役割の解明 (2012)
  • Author(s): 浅岡洋一
  • Organizer: 第34回日本比較生理生化学会,第21回吉田奨励賞受賞講演
  • Place of Presentation: 葉山
• [Presentation] 細胞の生死を制御するストレス応答性MKK7の神経系における生理的役割の解明 (2012)
  • Author(s): 山崎世和他
  • Organizer: 第21回日本Cell Death学会
  • Place of Presentation: 名古屋
• [Presentation] マウスとメダカから学ぶ肝形成と肝疾患 (2012)
  • Author(s): 仁科博史
  • Organizer: 秋田大学医学部セミナー
  • Place of Presentation: 秋田
• [Presentation] 神経細胞特異的欠損マウスを用いた概日リズム制御機構におけるストレス応答性キナーゼMKK7の機能解析 (2012)
  • Author(s): 有馬誉恵他
  • Organizer: 第11回次世代を担う若手ファーマ・バイオフォーラム
  • Place of Presentation: 福岡
• [Presentation] ストレス応答性MKK7-JNKシグナル経路による分子時計制御 (2012)
  • Author(s): 内田好海他
  • Organizer: 第11回ファーマバイオフォーラム2012
  • Place of Presentation: 福岡
• [Presentation] ストレス応答性リン酸化酵素による概日リズム制御 (2012)
  • Author(s): 平山順他
  • Organizer: 第19回日本時間生物学会学術大会
  • Place of Presentation: 札幌
• [Presentation] JNK signaling is required for the maintenance of motor performance in old-age animals (2012)
  • Author(s): 山崎世和他
  • Organizer: 第35回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] Light-dependentUV-tolerance in zebrafish early embryo (2012)
  • Author(s): 平山順他
  • Organizer: 第18回小型魚類研究会
  • Place of Presentation: 京都
• [Presentation] Analysis of the Hippo signaling pathway regulating neuronal differentiation in the retina (2012)
  • Author(s): 浅岡洋一他
  • Organizer: 第18回小型魚類研究会
  • Place of Presentation: 京都
• [Presentation] がん遺伝子YAPによる肝細胞癌発症機構の解明 (2012)
  • Author(s): 宮村憲央
  • Organizer: 第17回日本肝臓医生物学研究会
  • Place of Presentation: 旭川
• [Presentation] がん遺伝子YAP誘導性肝細胞がんのゲノム解析 (2012)
  • Author(s): 千葉恭敬
  • Organizer: 第17回日本肝臓医生物学研究会
  • Place of Presentation: 旭川
• [Presentation] YAPパラログTAZの肝がん誘導能の検討 (2012)
  • Author(s): 斎藤光介
  • Organizer: 第17回日本肝臓医生物学研究会
  • Place of Presentation: 旭川
• [Presentation] 器官サイズ制御因子YAPの網膜分化における機能解析 (2012)
  • Author(s): 浅岡洋一
  • Organizer: 第5回RRM
  • Place of Presentation: 東京
• [Presentation] がん遺伝子yap依存的異常肝細胞の排除と肝細胞がんの発症 (2012)
  • Author(s): 仁科博史
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] ストレス応答性キナーゼによる概日リズム制御 (2012)
  • Author(s): 平山順他
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] がん遺伝子産物YAPアセチル化サイクルの同定 (2012)
  • Author(s): 畠星治他
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
• [Presentation] ストレス応答性MAPキナーゼシグナル伝達系のゼブラフィッシュ初期胚における役割の解明 (2012)
  • Author(s): 浅岡洋一
  • Organizer: 第34回日本比較生理生化学会
  • Place of Presentation: 葉山
• [Remarks]
  • URL: http://www.tmd.ac.jp/mri/dbio/index.html