The novel anti-angiogenic therapy for hepatocellular carcinoma.

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590975
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Okayama University
• Principal Investigator: SHIRAHA Hidenori 岡山大学, 大学病院, 講師 (40379748)
• Co-Investigator(Kenkyū-buntansha): ONISHI Hideki 岡山大学, 大学院医歯薬学総合研究科, 助教 (30595468) ; NAKAMURA Shinichiro 岡山大学, 岡山大学病院, 助教 (70514230) ; NOUSO Kazuhiro 岡山大学, 大学院医歯薬学総合研究科, 准教授 (10314668) ; YAMAMOTO Kazuhide 岡山大学, 大学院医歯薬学総合研究科, 教授 (90140491)
• Co-Investigator(Renkei-kenkyūsha): MURATA Kazumoto 国立国際医療研究センタ-, 国府台病院・肝炎免疫 研究センタ-,大学院 医歯薬学総合研究科, 肝疾患先端治療室長,教授 (40345971)
• Project Period (FY): 2011 – 2013
• Keywords: 肝細胞癌 / Notchシグナル / 血管新生 / RUNX3

Research Abstract

Runt-related transcription factor 3 (RUNX3) expression was lost or decreased in hepatocellular carcinoma (HCC) cell lines and HCC tissues. Introduction of RUNX3 cDNA suppressed Notch signal in HCC cells. The loss of RUNX3 expression induced epithelial-mesenchymal transition (EMT) in HCC.
Gamma-glutamyl carboxy lase (GGCX) activity was decreased in des-gamma carboxyprothrombin (DCP)-positive HCC. DCP stimulated angiogenesis in HCC progression. DCP antibody successfully inhibited the tubular formation of the vascular endothelial cells. The decrement of GGCX activity also induced EMT in HCC.

Research Products

• [Journal Article] Efficacy of sorafenib beyond first progression in patients with metastatic hepatocellular carcinoma (2014)
  • Author(s): Miyahara K, Nouso K, Morimoto Y, Takeuchi Y, Hagihara H, Kuwaki K, Onishi H, Ikeda F, Miyake Y, Nakamura S, Shiraha H, Takaki A, Iwadou S, Kobayashi Y, Takaguchi K, Takuma Y, Takabatake H, Sakaguchi K, Yamamoto K
  • Journal Title: Hepatol Res Volume: 44(3) Pages: 296-301
  • DOI: 10.1111/hepr.12123
  • Peer Reviewed
• [Journal Article] Human hepatocyte carcinogenesis (2013)
  • Author(s): Shiraha H, Yamamoto K, Namba M
  • Journal Title: Int J Oncol Volume: 42(4) Pages: 1133-8
  • DOI: 10.3892/ijo.2013.1829
• [Journal Article] Evaluation of the effect of sorafenib using serum NX-des-γ-carboxyprothrombin in patients with hepatocellular carcinoma (2013)
  • Author(s): Miyahara K, Nouso K, Morimoto Y, Tomoda T, Kobayashi S, Takeuchi Y, Hagihara H, Kuwaki K, Ohnishi H, Ikeda F, Miyake Y, Nakamura S, Shiraha H, Takaki A, Yamamoto K
  • Journal Title: Hepatol Res Volume: 43(10) Pages: 1064-70
  • DOI: 10.1111/hepr.12055
  • Peer Reviewed
• [Journal Article] Loss of runt-related transcription factor 3 induces gemcitabine resistance in pancreatic cancer (2013)
  • Author(s): Horiguchi S, Shiraha H, Nagahara T, Kataoka J, Iwamuro M, Matsubara M, Nishina S, Kato H, Takaki A, Nouso K, Tanaka T, Ichimura K, Yagi T, Yamamoto K
  • Journal Title: Mol Oncol Pages: 840-9
  • DOI: 10.1016/j.molonc.2013.04.004
  • Peer Reviewed
• [Journal Article] Pro-angiogenic cytokines for prediction of outcomes in patients with advanced hepatocellular carcinoma (2013)
  • Author(s): Miyahara K, Nouso K, Morimoto Y, Takeuchi Y, Hagihara H, Kuwaki K, Onishi H, Ikeda F, Miyake Y, Nakamura S, Shiraha H, Takaki A, Honda M, Kaneko S, Sato T, Sato S, Obi S, Iwadou S, Kobayashi Y, Takaguchi K, Kariyama K, Takuma Y, Takabatake H, Yamamoto K
  • Journal Title: Br J Cancer Volume: 109(8) Pages: 2072-8
  • DOI: 10.1038/bjc.2013.554
  • Peer Reviewed
• [Journal Article] 腫瘍マーカーの発現メカニズムから考える肝癌治療の方向性 (2013)
  • Author(s): 白羽英則
  • Journal Title: クリニシアン Volume: 59(11) Pages: 1062-1068
  • URL: http://www.eisai.jp/medical/clinician/vol59/no613/
• [Journal Article] Risk factors for recurrence after transarterial chemoembolization for early-stage hepatocellular carcinoma (2012)
  • Author(s): Kinugasa H, Nouso K, Takeuchi Y, Yasunaka T, Onishi H, Nakamura S, Shiraha H, Kuwaki K, Hagihara H, Ikeda F, Miyake Y, Takaki A, Yamamoto K
  • Journal Title: J Gastroenterol Volume: 47(4) Pages: 421-6
  • DOI: 10.1007/s00535-011-0492-9
  • Peer Reviewed
• [Journal Article] Runt-related transcription factor 3 reverses epithelial-mesenchymal transition in hepatocellular carcinoma (2012)
  • Author(s): Tanaka S, Shiraha H, Nakanishi Y, Nishina S, Matsubara M, Horiguchi S, Takaoka N, Iwamuro M, Kataoka J, Kuwaki K, Hagihara H, Toshimori J, Ohnishi H, Takaki A, Nakamura S, Nouso K, Yagi T, Yamamoto K
  • Journal Title: Int J Cancer Volume: 131(11) Pages: 2537-46
  • DOI: 10.1002/ijc.27575
  • Peer Reviewed
• [Journal Article] Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice (2012)
  • Author(s): Kawai D, Takaki A, Nakatsuka A, Wada J, Tamaki N, Yasunaka T, Koike K, Tsuzaki R, Matsumoto K, Miyake Y, Shiraha H, Morita M, Makino H, Yamamoto K
  • Journal Title: Hepatology Volume: 56(3) Pages: 912-21
  • DOI: 10.1002/hep.25782
  • Peer Reviewed
• [Journal Article] Des-γ-carboxyl prothrombin is associated with tumor angiogenesis in hepatocellular carcinoma (2012)
  • Author(s): Matsubara M, Shiraha H, Kataoka J, Iwamuro M, Horiguchi S, Nishina S, Takaoka N, Uemura M, Takaki A, Nakamura S, Kobayashi Y, Nouso K, Yamamoto K
  • Journal Title: J Gastroenterol Hepatol Volume: 27(10) Pages: 1602-8
  • DOI: 10.1111/j.1440-1746.2012.07173.x
  • Peer Reviewed
• [Journal Article] Clinical utility of serum fucosylated hemopexin in Japanese patients with hepatocellular carcinoma (2012)
  • Author(s): Kobayashi S, Nouso K, Kinugasa H, Takeuchi Y, Tomoda T, Miyahara K, Hagihara H, Kuwaki K, Onishi H, Nakamura S, Ikeda F, Miyake Y, Shiraha H, Takaki A, Yamamoto K
  • Journal Title: Hepatol Res Volume: 42(12) Pages: 1187-95
  • DOI: 10.1111/j.1872-034X.2012.01044.x
  • Peer Reviewed
• [Journal Article] Prognostic importance of fucosylated alpha-fetoprotein in hepatocellular carcinoma patients with low alpha-fetoprotein (2011)
  • Author(s): Nouso K, Kobayashi Y, Nakamura S, Kobayashi S, Takayama H, Toshimori J, Kuwaki K, Hagihara H, Onishi H, Miyake Y, Ikeda F, Shiraha H, Takaki A, Iwasaki Y, Kobashi H, Yamamoto K
  • Journal Title: J Gastroenterol Hepatol Volume: 26(7) Pages: 1195-200
  • DOI: 10.1111/j.1440-1746.2011.06720.x
  • Peer Reviewed
• [Journal Article] Restored expression of the tumor suppressor gene RUNX3 reduces cancer stem cells in hepatocellular carcinoma by suppressing Jagged1-Notch signaling (2011)
  • Author(s): Nishina S, Shiraha H, Nakanishi Y, Tanaka S, Matsubara M, Takaoka N, Uemura M, Horiguchi S, Kataoka J, Iwamuro M, Yagi T, Yamamoto K
  • Journal Title: Oncol Rep Volume: 26(3) Pages: 523-31
  • DOI: 10.3892/or.2011.1336
  • Peer Reviewed
• [Journal Article] Predicting the treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular carcinoma (2011)
  • Author(s): Miyahara K, Nouso K, Tomoda T, Kobayashi S, Hagihara H, Kuwaki K, Toshimori J, Onishi H, Ikeda F, Miyake Y, Nakamura S, Shiraha H, Takaki A, Yamamoto K
  • Journal Title: J Gastroenterol Hepatol Volume: 26(11) Pages: 1604-11
  • DOI: 10.1111/j.1440-1746.2011.06887.x
  • Peer Reviewed
• [Journal Article] Hepatitis B virus core promoter mutations G1613A and C1653T are significantly associated with hepatocellular carcinoma in genotype C HBV-infected patients (2011)
  • Author(s): Tatsukawa M, Takaki A, Shiraha H, Koike K, Iwasaki Y, Kobashi H, Fujioka S, Sakaguchi K, Yamamoto K
  • Journal Title: BMC Cancer Volume: 11 Pages: 458
  • DOI: 10.1186/1471-2407-11-458
  • Peer Reviewed
• [Presentation] TACE不応症例への治療戦略の検討 (2013)
  • Author(s): 和田望,能祖一裕,中村進一郎,森元裕貴,竹内康人,安中哲也,萩原宏明,桑木健志,大西秀樹,白羽英則,高木章乃夫,山本和秀
  • Organizer: 第17回日本肝臓学会大会
  • Place of Presentation: 東京
  • Year and Date: 20131009-12
• [Presentation] 血清糖鎖マーカーによる進行肝細胞癌の予後予測 (2013)
  • Author(s): 宮原孝治,能祖一裕,森元裕貴,和田望,竹内康人,萩原宏明,桑木健志,大西秀樹,中村進一郎,白羽英則,天野麻穂,西村紳一郎,山本和秀
  • Organizer: 第17回日本肝臓学会大会
  • Place of Presentation: 東京
  • Year and Date: 20131009-12
• [Presentation] 肝細胞癌遠隔転移と血小板の関係 (2013)
  • Author(s): 森元裕貴,能祖一裕,和田望,竹内康人,宮原孝治,萩原宏明,桑木健志,安中哲也,大西秀樹,三宅康広,中村進一郎,白羽英則,高木章乃夫,山本和秀
  • Organizer: 第17回日本肝臓学会大会
  • Place of Presentation: 東京
  • Year and Date: 20131009-12
• [Presentation] 肝癌におけるRUNX3発現低下はNotchシグナルを介し癌幹細胞化とEMTを制御する (2013)
  • Author(s): 白羽英則,片岡淳朗,堀口繁,岩室雅也,永原照也,内田大輔,仁科慎一,高木章乃夫,萩原宏明,桑木健志,大西秀樹,中村進一郎,能祖一裕,山本和秀
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 20130606-07
• [Presentation] ソラフェニブ中止に伴う腫瘍進展に関する検討 (2013)
  • Author(s): 宮原孝治,能祖一裕,森元裕貴,竹内康人,和田望,萩原宏明,安中哲也,桑木健志,大西秀樹,池田房雄,三宅康広,中村進一郎,白羽英則,高木章乃夫,山本和秀
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 20130606-07
• [Presentation] Deactivation of GGCX induced epitheliam-mesenchymal transition in hepatocellular carcinoma (2012)
  • Author(s): Hidenori Shiraha, Junro Kataoka, Shinichiro Nakamura, Kazuhiro Nouso, Shigeru Horiguchi, et.al
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 20120919-21
• [Presentation] Multi drug resistant protein expression correlates with epitheliam-mesenchymal transition in hepatocellular carcinoma (2012)
  • Author(s): Junro Kataoka, Hidenori Shiraha, Shinichiro Nakamura, Kazuhiro Nouso, Shigeru Horiguchi, et.al
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 20120919-21
• [Presentation] 肝癌におけるカルボキシラーゼ活性低下と細胞接着低下およびEMTとの関連 (2012)
  • Author(s): 白羽英則
  • Organizer: 第29回犬山シンポジウム
  • Place of Presentation: 愛知県犬山市
  • Year and Date: 20120802-03
  • Invited
• [Presentation] RUNX3発現低下は、肝細胞癌における5-FUとcisplatinの耐性化を誘導する (2012)
  • Author(s): 片岡淳朗,白羽英則,永原照也,岩室雅也,堀口繁,松原稔,山本和秀
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
  • Year and Date: 20120607-08
• [Presentation] 肝細胞癌において、カルボキシラーゼ活性低下は、SPARC発現を誘導し、細胞接着低下、EMT進行を引き起こす (2012)
  • Author(s): 白羽英則,堀口繁,岩室雅也,片岡淳朗,永原照也,高木章乃夫,萩原宏明,桑木健志,大西秀樹,中村進一郎,能祖一裕,山本和秀
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
  • Year and Date: 20120607-08
• [Presentation] 非B非C肝癌の予後及び特徴 (2012)
  • Author(s): 竹内康人,能祖一裕,萩原宏明,安中哲也,桑木健志,大西秀樹,池田房雄,中村進一郎,白羽英則,三宅康広,高木章乃夫,山本和秀
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
  • Year and Date: 20120607-08
• [Presentation] Streptozotocin投与NASH発癌モデルマウスにおける病態進行と水素水投与の有効性の検討 (2012)
  • Author(s): 河合大介,高木章乃夫,山本和秀,中司敦子,和田淳,玉木直文,安中哲也,小池和子,津崎龍一郎,松本和幸,三宅康広,白羽英則,森田学,槇野博史
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 東京
  • Year and Date: 20120419-21
• [Presentation] 肝細胞癌におけるPIVKA-II産生とEpithelial-Mesenchymal Transition (2011)
  • Author(s): 白羽英則,松原稔,堀口繁,岩室雅也,片岡淳朗,永原照也,高木章乃夫,萩原宏明,桑木健志,大西秀樹,中村進一郎,能祖一裕,山本和秀
  • Organizer: JDDW2011
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-21
• [Presentation] 血管新生関連サイトカインによる進行肝細胞癌の治療効果予測 (2011)
  • Author(s): 宮原孝治,能祖一裕,衣笠秀明,竹内康人,友田健,小林沙代,萩原宏明,安中哲也,桑木健志,大西秀樹,池田房雄,三宅康広,中村進一郎,白羽英則,高木章乃夫,山本和秀
  • Organizer: JDDW2011
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-21
• [Presentation] RUNX3発現低下は、HCCにおける5-FUとcisplatinに対する抗癌耐性化を誘導する (2011)
  • Author(s): 片岡淳朗,白羽英則,永原照也,堀口繁,岩室雅也,松原稔,山本和秀
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-04
• [Presentation] 肝細胞癌におけるepithelial-mesenchymal transition制御 (2011)
  • Author(s): 白羽英則,仁科慎一,堀口繁,片岡淳朗,岩室雅也,松原稔,高岡伸行,高木章乃夫,大西秀樹,中村進一郎,能祖一裕,山本和秀
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-04
• [Remarks]
  • URL: http://www.okayama-gastro.com/medical/research1.php