Translational research focusing on the regulation of proteasome by Gankyrin

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590998
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kinki University
• Principal Investigator: SAKURAI Toshiharu 近畿大学, 医学部, 講師 (90397539)
• Co-Investigator(Kenkyū-buntansha): KUDO Masatoshi 近畿大学, 医学部, 教授 (10298953)
• Co-Investigator(Renkei-kenkyūsha): FUJITA Jun 京都大学, 医学研究科, 教授 (50173430)
• Project Period (FY): 2011 – 2013
• Keywords: ガンキリン / 幹細胞 / 炎症と発癌

Research Abstract

Liver-specific p38-alpha ablation was found to enhance ROS accumulation, because it reduced the expression ofHSP25. p38-alpha-deficiency also increased the expression of SOX2, c-Jun and Gankyrin and led to enhanced TAA-induced hepatocarcinogenesis. The up-regulation of SOX2 and c-Jun was prevented by administration of the antioxidant butylated hydroxyanisole. The risk of human HCC recurrence is positively correlated with ROS accumulation in the liver. Augmented oxidative stress of liver parenchymal cells may explain the close relationship between liver fibrosis and hepatocarcinogenesis. In addition, expression of CD133, a cancer stem cell marker, was significantly correlated with Gankyrin expression. Gankyrin knockdown decreased the expression of vascular endothelial growth factor (VEGF) and stemness factors such as Nanog and Oct-4 in colorectal and liver cancer cells.

Research Products

• [Journal Article] Molecular Link between Liver Fibrosis and Hepatocellular Carcinoma (2013)
  • Author(s): Sakurai T, Kudo M
  • Journal Title: Liver Cancer Volume: 2 Pages: 365-366
  • Peer Reviewed
• [Journal Article] Reactive Oxygen Species Induce Epigenetic Instability through the Formation of 8-Hydroxydeoxyguanosine in Human Hepatocarcinogenesis (2013)
  • Author(s): Nishida N, Arizumi T, Takita M, Kitai S, Yada N, Hagiwara S, Inoue T, Minami Y, Ueshima K, Sakurai T, Kudo M
  • Journal Title: Dig Dis Volume: 31(5-6) Pages: 459-66
  • Peer Reviewed
• [Journal Article] Hypothermia Protects against Fulminant Hepatitis in Mice by Reducing Reactive Oxygen Species Production (2013)
  • Author(s): Sakurai T, Kudo M, Watanabe T, Itoh K, Higashitsuji H, Arizumi T, Inoue T, Hagiwara S, Ueshima K, Nishida N, Fukumoto M, Fujita J
  • Journal Title: Dig Dis Volume: 31(5-6) Pages: 440-6
  • Peer Reviewed
• [Journal Article] Unique Association between Global DNA Hypomethylation and Chromosomal Alterations in Human Hepatocellular Carcinoma (2013)
  • Author(s): Nishida N, Kudo M, Nishimura T, Arizumi T, Takita M, Kitai S, Yada N, Hagiwara S, Inoue T, Minami Y, Ueshima K, Sakurai T, Yokomichi N, Nagasaka T, Goel A
  • Journal Title: PLoS One Volume: 8(9) Pages: 72312
  • Peer Reviewed
• [Journal Article] Impact of peginterferon alpha-2b and entecavir hydrate combination therapy on persistent viral suppression in patients with chronic hepatitis B (2013)
  • Author(s): Hagiwara S, Kudo M, Osaki Y, Matsuo H, Inuzuka T, Matsumoto A, Tanaka E, Sakurai T, Ueshima K, Inoue T, Yada N, Nishida N
  • Journal Title: J Med Virol Volume: 85(6) Pages: 987-95
  • Peer Reviewed
• [Journal Article] Association of Gankyrin and stemness factor expression in human colorectal cancer (2013)
  • Author(s): Mine H, Sakurai T, Kashida H, Matsui S, Nishida N, Nagai T, Hagiwara S, Watanabe T, Kudo M
  • Journal Title: Dig Dis Sci Volume: 58(8) Pages: 2337-44
  • Peer Reviewed
• [Journal Article] Overexpression of gankyrin in mouse hepatocytes induces hemangioma by suppressing factor inhibiting hypoxia-inducible factor-1 (FIH-1) and activating hypoxia-inducible factor-1 (2013)
  • Author(s): Liu Y, Higashitsuji H, Higashitsuji H, Itoh K, Sakurai T, Koike K, Hirota K, Fukumoto M, Fujita J
  • Journal Title: Biochem Biophys Res Commun Volume: 432 Pages: 22-7
  • Peer Reviewed
• [Journal Article] p38αInhibits Liver Fibrogenesis and Consequent Hepatocarcinogenesis by Curtailing Accumulation of Reactive Oxygen Species (2013)
  • Author(s): Sakurai T, Kudo M, Umemura A, He G, Elsharkawy AM, Seki E, Karin M
  • Journal Title: Cancer Res Volume: 73(1) Pages: 215-24
  • Peer Reviewed
• [Journal Article] Heat shock protein 27 expression is inversely correlated with atrophic gastritis and intraepithelial neoplasia (2013)
  • Author(s): Nagata Y, Kudo M, Nagai T, Watanabe T, Kawasaki M, Asakuma Y, Hagiwara S, Nishida N, Matsui S, Kashida H, Sakurai T
  • Journal Title: Dig Dis Sci Volume: 58 Pages: 381-8
  • Peer Reviewed
• [Journal Article] FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma (2013)
  • Author(s): Arao T, Ueshima K, Matsumoto K, Nagai T, Kimura H, Hagiwara S, Sakurai T, Haji S, Kanazawa A, Hidaka H, Iso Y, Kubota K, Shimada M, Utsunomiya T, Hirooka M, Hiasa Y, Toyoki Y, Hakamada K, Yasui K, Kumada T, Toyoda H, Sato S, Hisai H, Kuzuya T, Tsuchiya K, Izumi N, Arii S, Nishio K, Kudo M
  • Journal Title: Hepatology Volume: 57 Pages: 1407-15
  • Peer Reviewed
• [Journal Article] Quantification of tumor DNA in serum and vascular invasion of human hepatocellular carcinoma (2013)
  • Author(s): Nishida N, Arizumi T, Takita M, Nagai T, Kitai S, Yada N, Hagiwara S, Inoue T, Minami Y, Ueshima K, Sakurai T, Ida H, Kudo M
  • Journal Title: Oncology Volume: 1 Pages: 82-7
  • Peer Reviewed
• [Journal Article] Usefulness of Contrast-Enhanced Ultrasonography to Evaluate the Post-Treatment Responses of Radiofrequency Ablation for Hepatocellular Carcinoma : Comparison with Dynamic CT (2013)
  • Author(s): Inoue T, Kudo M, Hatanaka K, Arizumi T, Takita M, Kitai S, Yada N, Hagiwara S, Minami Y, Sakurai T, Ueshima K, Nishida N
  • Journal Title: Oncology Volume: 1 Pages: 51-7
  • Peer Reviewed
• [Journal Article] Risk of Hepatocellular Carcinoma Development in Cases of Hepatitis C Treated by Long-Term, Low-Dose PEG-IFNα-2a (2012)
  • Author(s): Hagiwara S, Sakurai T, Takita M, Ueshima K, Minami Y, Inoue T, Yada N, Kitai S, Nagai T, Hayaishi S, Arizumi T, Nishida N, Kudo M
  • Journal Title: Dig Dis Volume: 30 Pages: 561-7
  • Peer Reviewed
• [Journal Article] Gender differences in the livers of patients with hepatocellular carcinoma and chronic hepatitis C infection (2012)
  • Author(s): Nishida N, Arizumi T, Hayaishi S, Takita M, Kitai S, Yada N, Hagiwara S, Inoue T, Minami Y, Ueshima K, Sakurai T, Ikai I, Kudo M
  • Journal Title: Dig Dis Volume: 30 Pages: 547-53
  • Peer Reviewed
• [Journal Article] Characteristic Pattern of Reactivation of Hepatitis B Virus during Chemotherapy for Solid Cancers (2012)
  • Author(s): Hagiwara S, Sakurai T, Nishina S, Tanaka K, Ikeda M, Ueshima K, Minami Y, Inoue T, Yada N, Kitai S, Takita M, Nagai T, Hayaishi S, Arizumi T, Park AM, Munakata H, Nishida N, Kudo M
  • Journal Title: Dig Dis Volume: 30 Pages: 541-6
  • Peer Reviewed
• [Journal Article] Identification of a novel enhancer that binds Sp1 and contributes to induction of cold-inducible RNA-binding protein (cirp) expression in mammalian cells (2012)
  • Author(s): Sumitomo Y, Higashitsuji H, Higashitsuji H, Liu Y, Fujita T, Sakurai T, Candeias MM, Itoh K, Chiba T, Fujita J
  • Journal Title: BMC Biotechnol Volume: 12 Pages: 72
  • Peer Reviewed
• [Journal Article] Cold-inducible RNA-binding protein (Cirp) interacts with Dyrk1b/Mirk and promotes proliferation of immature male germ cells in mice (2012)
  • Author(s): Masuda T, Itoh K, Higashitsuji H, Higashitsuji H, Nakazawa N, Sakurai T, Liu Y, Tokuchi H, Fujita T, Zhao Y, Nishiyama H, Tanaka T, Fukumoto M, Ikawa M, Okabe M, Fujita J
  • Journal Title: Proc Natl Acad Sci U S A Volume: 109 Pages: 10885-90
  • Peer Reviewed
• [Journal Article] Toll-like receptor activation in basophils contributes to the development of IgG4-related disease (2012)
  • Author(s): Watanabe T, Yamashita K, Sakurai T, Kudo M, Shiokawa M, Uza N, Kodama Y, Uchida K, Okazaki K, Chiba T
  • Journal Title: J Gastroenterol Volume: 48 Pages: 247-53
  • Peer Reviewed
• [Journal Article] Activation of JNK and High Expression Level of CD133 Predict a Poor Response to Sorafenib in Hepatocellular Carcinoma (2012)
  • Author(s): Hagiwara S, Kudo M, Nagai T, Inoue T, Ueshima K, Nishida N, Watanabe T, Sakurai T
  • Journal Title: Br J Cancer Volume: 106 Pages: 1997-2003
  • Peer Reviewed
• [Journal Article] p38MAPK suppresses chronic pancreatitis by regulating HSP27 and BAD expressions (2012)
  • Author(s): Park AM, Kudo M, Hagiwara S, Tabuchi M, Watanabe T, Munakata H, Sakurai T
  • Journal Title: Free Radical Biol Med Volume: 52 Pages: 2284-2291
  • Peer Reviewed
• [Journal Article] Assessment of Gd-EOB-DTPA-enhanced MRI for HCC and dysplastic nodules and comparison of detection sensitivity versus MDCT (2012)
  • Author(s): Inoue T, Kudo M, Komuta M, Hayaishi S, Ueda T, Takita M, Kitai S, Hatanaka K, Yada N, Hagiwara S, Chung H, Sakurai T, Ueshima K, Sakamoto M, Maenishi O, Hyodo T, Okada M, Kumano S, Murakami T
  • Journal Title: J Gastroenterol Volume: 47(9) Pages: 1036-47
  • Peer Reviewed
• [Journal Article] Activation of JNK in the non-cancerous liver tissue predicts a high risk of recurrence after hepatic resection (2012)
  • Author(s): Hagiwara S, Kudo M, Chung H, Ueshima K, Haji S, Watanabe T, Park AM, Munakata H, Sakurai T
  • Journal Title: Hepatol Res Volume: 42 Pages: 394-400
  • Peer Reviewed
• [Journal Article] Adriamycin Enhances Proteasome-Mediated Generation of the Proapoptotic Processed Form of MAGE-A4 in Hepatoma Cells (2011)
  • Author(s): Sakurai T, Kudo M, Itoh K, Ryu U, Higashitsuji H, Fujita J
  • Journal Title: Oncology Volume: 81 (Suppl 1) Pages: 30-5
  • Peer Reviewed
• [Journal Article] Signaling pathways governing tumor angiogenesis (2011)
  • Author(s): Sakurai T, Kudo M
  • Journal Title: Oncology Volume: 81 (Suppl 1) Pages: 24-9
  • Peer Reviewed
• [Journal Article] Association of interleukin-28B and hepatitis C genotype 1 with a high viral load and response to pegylated interferon plus ribavirin therapy (2011)
  • Author(s): Sakurai T, Kudo M
  • Journal Title: Digestion Volume: 84 (Suppl 1) Pages: 56-61
  • Peer Reviewed
• [Journal Article] Involvement of activation of toll-like receptors and NOD-like receptors is involved in enhanced IgG4 responses in autoimmune pancreatitis (2011)
  • Author(s): Watanabe T, Yamashita K, Fujikawa S, Sakurai T, Kudo M, Shiokawa M, Kodama Y, Uchida K, Okazaki K, Chiba T
  • Journal Title: Arthritis Rheum Volume: 64 Pages: 914-24
  • Peer Reviewed
• [Journal Article] Des-γ-Carboxyprothrombin May Be a Promising Biomarker to Determine the Therapeutic Efficacy of Sorafenib for Hepatocellular Carcinoma (2011)
  • Author(s): Ueshima K, Kudo M, Takita M, Nagai T, Tatsumi C, Ueda T, Kitai S, Ishikawa E, Yada N, Inoue T, Hagiwara S, Minami Y, Chung H, Sakurai T
  • Journal Title: Digestion Volume: 29 Pages: 321-325
  • Peer Reviewed
• [Journal Article] Involvement of angiotensin II and reactive oxygen species in pancreatic fibrosis (2011)
  • Author(s): Sakurai T, Kudo M, Fukuta N, Nakatani T, Kimura M, Park AM, Munakata H
  • Journal Title: Pancreatology Volume: 11 (suppl 2) Pages: 7-13
  • Peer Reviewed
• [Presentation] 肝発癌および治療抵抗性獲得における幹細胞の役割 (2013)
  • Author(s): 櫻井俊治, 他
  • Organizer: Japan Digestive Disease Week 2013ワークショップ
  • Place of Presentation: 東京
  • Year and Date: 2013-10-11
• [Presentation] 大腸発癌における幹細胞の制御機構 (2013)
  • Author(s): 櫻井俊治, 他
  • Organizer: 日本消化器癌発生学会総会シンポジウム
  • Place of Presentation: 金沢
  • Year and Date: 2013-09-05
• [Presentation] 胃粘膜上皮のHSPA27発現は上皮内癌の発生リスクと負の相関を示す (2013)
  • Author(s): 永田嘉昭、櫻井俊治, 他
  • Organizer: 第99回日本消化器病学会総会
  • Place of Presentation: 鹿児島
  • Year and Date: 2013-03-23
• [Presentation] 慢性膵炎におけるp38MAPK, HSPA27の役割 (2013)
  • Author(s): 櫻井俊治, 他
  • Organizer: 第99回日本消化器病学会総会
  • Place of Presentation: 鹿児島
  • Year and Date: 2013-03-21
• [Presentation] Activation of JNK in the non-cancerous liver tissue predicts a high risk of recurrence after hepatic resection for hepatocellular carcinoma (2012)
  • Author(s): 櫻井俊治, 他
  • Organizer: Digestive Disease Week 2012
  • Place of Presentation: 米国サンディエゴ
  • Year and Date: 2012-05-21
• [Presentation] 肝細胞癌治療におけるJNK活性の重要性 (2011)
  • Author(s): 萩原智、櫻井俊治、工藤正俊
  • Organizer: 日本肝臓学会総会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2011-06-02
• [Book] シグナル伝達異常とバイオマーカー探索 (2012)
  • Author(s): 櫻井俊治, 他
  • Total Pages: 35-39
  • Publisher: The Liver Cancer Journal
• [Book] トップランナーに聞く (2011)
  • Author(s): 櫻井俊治, 他
  • Total Pages: 1207-1210
  • Publisher: 最新医学社