Novel molecular target in colorectal cancer and inflammatory bowel disease

• Project/Area Number: 26460979
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kindai University
• Principal Investigator: SAKURAI Toshiharu 近畿大学, 医学部, 講師 (90397539)
• Co-Investigator(Kenkyū-buntansha): 工藤 正俊 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): 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: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 大腸癌 / 炎症性腸疾患 / ストレス応答 / ガンキリン / 癌 / 炎症性発癌 / プロテアソーム

Outline of Final Research Achievements

We analyzed gene expression of colon tissues obtained from 354 patients with IBD and CAC and found that expression of gankyrin was much higher in colonic mucosa of patients with refractory IBD than in those with IBD in remission. Expression of gankyrin was upregulated in inflammatory cells as well as tumor cells in colonic mucosa of patients with CAC. The interaction between ganlyrin and SHP-1 leads to inhibition of STAT3 activation and to enhancement of TNF-alpha and IL-17 in inflammatory cells. We created mice with intestinal epithelial cell-specific gankyrin ablation and deletion of gankyrin in myeloid and epithelial cells. Gankyrin deficiency in myeloid cells reduced the activity of ERK and the expression of stem cell markers, leading to attenuated tumorigenic potential. These findings provide important insights into the pathogenesis of CAC and suggest that gankyrin is a promising target for developing therapeutic and preventive strategies against CAC.

Research Products

• [Journal Article] The oncoprotein gankyrin promotes the development of colitis-associated cancer through activation of STAT3. (2017)
  • Author(s): Sakurai T, Higashitsuji H, Kashida H, Watanabe T, Komeda Y, Nagai T, Hagiwara S, Kitano M, Nishida N, Abe T, Kiyonari H, Itoh K, Fujita J, Kudo M.
  • Journal Title: Oncotarget Volume: Feb 1. Issue: 15 Pages: 24762-24776
  • DOI: 10.18632/oncotarget.14983
  • NAID: 120006355736
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Stress Response Protein RBM3 Promotes the Development of Colitis-associated Cancer. (2017)
  • Author(s): Sakurai T, Kashida H, Komeda Y, Nagai T, Hagiwara S, Watanabe T, Kitano M, Nishida N, Fujita J, Kudo M.
  • Journal Title: Inflam Bowel Dis Volume: 23 Issue: 1 Pages: 66-74
  • DOI: 10.1097/mib.0000000000000987
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Removal of diminutive colorectal polyps: A prospective randomized clinical trial between cold snare polypectomy and hot forceps biopsy. (2017)
  • Author(s): Komeda Y, Kashida H, Sakurai T, Tribonias G, Okamoto K, Kono M, Yamada M, Adachi T, Mine H, Nagai T, Asakuma Y, Hagiwara S, Matsui S, Watanabe T, Kitano M, Chikugo T, Chiba Y, Kudo M.
  • Journal Title: World J Gastroenterol. Volume: 14 Issue: 2 Pages: 328-335
  • DOI: 10.3748/wjg.v23.i2.328
  • Peer Reviewed / Open Access
• [Journal Article] Chronic Fibro-Inflammatory Responses in Autoimmune Pancreatitis Depend on IFN-α and IL-33 Produced by Plasmacytoid Dendritic Cells. (2017)
  • Author(s): Watanabe T, Yamashita K, Arai Y, Minaga K, Kamata K, Nagai T, Komeda Y, Takenaka M, Hagiwara S, Ida H, Sakurai T, Nishida N, Strober W, Kudo M.
  • Journal Title: J Immunol Volume: 印刷中 Issue: 10 Pages: 3886-3896
  • DOI: 10.4049/jimmunol.1700060
  • Peer Reviewed / Open Access
• [Journal Article] Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of submucosal tumors of the upper gastrointestinal tract. (2017)
  • Author(s): Kamata K, Takenaka M, Kitano M, Omoto S, Miyata T, Minaga K, Yamao K, Imai H, Sakurai T, Watanabe T, Nishida N, Chikugo T, Chiba Y, Imamoto H, Yasuda T, Lisotti A, Fusaroli P, Kudo M.
  • Journal Title: J Gastroenterol Hepatol. Volume: 印刷中 Issue: 10 Pages: 1686-1692
  • DOI: 10.1111/jgh.13766
  • Peer Reviewed
• [Journal Article] Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis: Long-term outcomes after removal of a self-expandable metal stent. (2017)
  • Author(s): Kamata K, Takenaka M, Kitano M, Omoto S, Miyata T, Minaga K, Yamao K, Imai H, Sakurai T, Watanabe T, Nishida N, Kudo M.
  • Journal Title: World J Gastroenterol. Volume: 23 Issue: 4 Pages: 661-667
  • DOI: 10.3748/wjg.v23.i4.661
  • Peer Reviewed
• [Journal Article] Nucleotide-binding oligomerization domain 1 acts in concert with the cholecystokinin receptor agonist, cerulein, to induce IL-33-dependent chronic pancreatiti (2016)
  • Author(s): Watanabe T, Sadakane Y, Yagama N, Sakurai T, Ezoe H, Kudo M, Chiba T, Strober W
  • Journal Title: Mucosal Immunol. Volume: in press Issue: 5 Pages: 1234-49
  • DOI: 10.1038/mi.2015.144
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cold-inducible RNA-binding protein (Cirp) promotes the development of liver cancer. (2015)
  • Author(s): Sakurai T, Yada N, Watanabe T, Arizumi T, Hagiwara S, Ueshima K, Nishida N, Fujita J, Kudo M.
  • Journal Title: Cancer Sci Volume: in press Issue: 4 Pages: 352-358
  • DOI: 10.1111/cas.12611
  • Peer Reviewed / Open Access
• [Journal Article] Heat shock protein A4/Apg-2 is required for stem/progenitor cell maintenance in intestinal inflammation. (2015)
  • Author(s): Adachi T, Sakurai T, Kashida H, Mine H, Hagiwara S, Matsui S, Yoshida K, Nishida N, Watanabe T, Itoh K, Fujita J, Kudo M.
  • Journal Title: Inflammatory Bowel Disease Volume: 21 Issue: 1 Pages: 31-39
  • DOI: 10.1097/mib.0000000000000244
  • Peer Reviewed / Open Access
• [Journal Article] Heat shock protein A4 controls cell migration and gastric ulcer healing. (2015)
  • Author(s): Sakurai T, Kashida H, Hagiwara S, Nishida N, Watanabe T, Fujita J, Kudo M.
  • Journal Title: Dig Dis Sci. Volume: 60 Issue: 4 Pages: 850-857
  • DOI: 10.1007/s10620-015-3561-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] mpaired expression of ATP-binding cassette transporter G2 and liver damage in erythropoietic protoporphyria (2015)
  • Author(s): Hagiwara S, Nishida N, Park AM, Sakurai T, Kawada A
  • Journal Title: Hepatology Volume: 62 Issue: 5 Pages: 1638-1639
  • DOI: 10.1002/hep.27871
  • Peer Reviewed / Open Access
• [Journal Article] 自己免疫性膵炎の診断について 診断基準の変遷と診断の現状 (2015)
  • Author(s): 内田 一茂, 岡崎 和一
  • Journal Title: 日本臨床免疫学会雑誌 Volume: 38 Issue: 7 Pages: 127-134
  • DOI: 10.4049/jimmunol.1500971
  • NAID: 130005089220
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Heat Shock Protein A4 Controls Cell Migration and Gastric Ulcer Healing. (2015)
  • Author(s): Sakurai T, Kashida H, Hagiwara S, Nishida N, Watanabe T, Fujita J, Kudo M.
  • Journal Title: Dig Dis Sci. Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6. (2014)
  • Author(s): Watanabe T, Asano N, Meng G, Yamashita K, Arai Y, Sakurai T, Kudo M, Fuss IJ, Kitani A, Shimosegawa T, Chiba T, Strober W.
  • Journal Title: Mucosal Immunol Volume: 1 Issue: 6 Pages: 1-1
  • DOI: 10.1038/mi.2014.19
  • Peer Reviewed / Open Access
• [Journal Article] Stress response protein Cirp links inflammation and tumorigenesis in colitis-associated cancer. (2014)
  • Author(s): Sakurai T, Kashida H, Watanabe T, Hagiwara S, Mizushima T, Iijima H, Nishida N, Higashitsuji H, Fujita J, Kudo M.
  • Journal Title: Cancer Res Volume: 74 Issue: 21 Pages: 6119-6128
  • DOI: 10.1158/0008-5472.can-14-0471
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide profiling of DNA methylation and tumor progression in human hepatocellular carcinoma. (2014)
  • Author(s): Nishida N*, Nishimura T, Nakai T, Chishina H, 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: 32 Issue: 6 Pages: 658-663
  • DOI: 10.1159/000367982
  • Peer Reviewed / Open Access
• [Journal Article] Duration of stable disease is associated with overall survival in patients with advanced hepatocellular carcinoma treated with sorafenib. (2014)
  • Author(s): Arizumi T, Ueshima K, Chishina H, Kono M, Takita M, Kitai S, Inoue T, Yada N, Hagiwara S, Minami Y, Sakurai T, Nishida N, Kudo M.
  • Journal Title: Dig Dis. Volume: 32 Issue: 6 Pages: 705-710
  • DOI: 10.1159/000368006
  • Peer Reviewed / Open Access
• [Journal Article] Decreased blood flow after sorafenib administration is an imaging biomarker to predict overall survival in patients with advanced hepatocellular carcinoma. (2014)
  • Author(s): Arizumi T, Ueshima K, Chishina H, Kono M, Takita M, Kitai S, Inoue T, Yada N, Hagiwara S, Minami Y, Sakurai T, Nishida N, Kudo M.
  • Journal Title: Dig Dis. Volume: 32 Issue: 6 Pages: 733-739
  • DOI: 10.1159/000368013
  • Peer Reviewed / Open Access
• [Journal Article] Identification of the epigenetically inactivated genes in human hepatocellular carcinoma by integrative analyses of methylation profiling and pharmacological unmasking. (2014)
  • Author(s): Nishida N, Chishina H, 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: 32 Issue: 6 Pages: 740-746
  • DOI: 10.1159/000368015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Validation of the Criteria of Transcatheter Arterial Chemoembolization Failure or Refractoriness in Patients with Advanced Hepatocellular Carcinoma Proposed by the LCSGJ. (2014)
  • Author(s): Arizumi T, Ueshima K, Chishina H, Kono M, Takita M, Kitai S, Inoue T, Yada N, Hagiwara S, Minami Y, Sakurai T, Nishida N, Kudo M.
  • Journal Title: Oncology Volume: 87 Issue: Suppl. 1 Pages: 32-36
  • DOI: 10.1159/000368143
  • Peer Reviewed / Open Access
• [Journal Article] Ultrasound elastography correlates treatment response by antiviral therapy in patients with chronic hepatitis C. (2014)
  • Author(s): Yada N, Sakurai T, Minami T, Arizumi T, Takita M, Inoue T, Hagiwara S, Ueshima K, Nishida N, Kudo M.
  • Journal Title: Oncology Volume: 87 Issue: Suppl. 1 Pages: 118-123
  • DOI: 10.1159/000368155
  • Peer Reviewed / Open Access
• [Presentation] The oncoprotein gankyrin promotes the development of colitis-associated cancer by mediating STAT3 activation. (2016)
  • Author(s): Toshiharu Sakurai
  • Organizer: Digestive Disease Week 2016
  • Place of Presentation: San Diego, U.S.A.
  • Int'l Joint Research
• [Presentation] Endoscopic diagnosis and treatment of early colorectal cancer in Japan. (2016)
  • Author(s): Toshiharu Sakurai
  • Organizer: The 5th JGES-ASGE Joint Symposium
  • Place of Presentation: 京王プラザホテル（新宿）
  • Int'l Joint Research
• [Presentation] 癌遺伝子ガンキリンは炎症をコントロールすることで大腸癌発生を促進する (2016)
  • Author(s): 櫻井俊治
  • Organizer: 日本癌学会総会
  • Place of Presentation: パシフィコ横浜 （横浜）
• [Presentation] 既存治療の効果予測の可能性 (2016)
  • Author(s): 櫻井俊治
  • 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（新宿）
• [Presentation] Magnifying Endoscopy and Treatment of GI Cancers (2016)
  • Author(s): Toshiharu Sakurai
  • Organizer: ENDOCON 2016, the 17th Annual Conference of Society of Gastrointestinal Endoscopy of India
  • Place of Presentation: Munbai, India
  • Int'l Joint Research / Invited
• [Presentation] Early Gastric Cancers. How to improve detection and characterization then treatment (2016)
  • Author(s): Toshiharu Sakurai
  • Organizer: ENDOCON 2016, The 17th Annual Conference of SGEI
  • Place of Presentation: Munbai, India
  • Int'l Joint Research / Invited
• [Presentation] The oncoprotein gankyrin links inflammation and tumorigenesis (2016)
  • Author(s): Toshiharu Sakurai
  • Organizer: Asian Pacific Digestive Week 2016
  • Place of Presentation: 神戸コンベンションセンター（神戸）
  • Int'l Joint Research
• [Presentation] Endoscopic diagnosis of submucosally invasive colorectal cancer (2015)
  • Author(s): 櫻井俊治
  • Organizer: 第89回日本消化器内視鏡学会総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-05-29
• [Presentation] 肝発癌におけるストレス応答蛋白Cirpの役割 (2015)
  • Author(s): 櫻井俊治
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 福岡鶴屋東館
  • Year and Date: 2015-05-21
• [Presentation] Stress response links inflammation and tumorigenesis in inflammatory bowel disease (2015)
  • Author(s): 櫻井俊治
  • Organizer: Digestive Disease Week 2015
  • Place of Presentation: Walter E Washington Convention Center (USA)
  • Year and Date: 2015-05-18
  • Int'l Joint Research
• [Presentation] Stress response links inflammation and tumorigenesis in colitis-associated cancer. (2014)
  • Author(s): 櫻井俊治
  • Organizer: 第25回消化器癌発生学会
  • Place of Presentation: ホテル日航福岡
  • Year and Date: 2014-11-13
• [Presentation] Heat shock protein A4 controls gastric ulcer healing and metastasis of gastric cancer. (2014)
  • Author(s): 櫻井俊治
  • Organizer: JDDW2014
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2014-10-24
• [Presentation] The role of stress response protein in intestinal mucosal defense (2014)
  • Author(s): 櫻井俊治
  • Organizer: JDDW2014
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2014-10-23
• [Presentation] Stress response links inflammation and tumorigenesis in colitis-associated cancer. (2014)
  • Author(s): 櫻井俊治
  • Organizer: JDDW2014
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2014-10-23
• [Presentation] Stress response links inflammation and tumorigenesis in colitis-associated cancer. (2014)
  • Author(s): 櫻井俊治
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-27
• [Book] Medical Practice (2015)
  • Author(s): 櫻井俊治、工藤正俊
  • Total Pages: 7
  • Publisher: 文光堂