Novel molecular target in colorectal cancer and inflammatory bowel disease

2016 Fiscal Year Annual Research Report

• Project/Area Number: 26460979
• Research Institution: Kindai University
• Principal Investigator: 櫻井 俊治 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)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: ガンキリン / ストレス応答 / 癌

Outline of Annual Research Achievements

難治化した炎症性腸疾患（IBD）において長期間の炎症が大腸発癌を促進し、B型肝炎や非アルコール性脂肪肝炎(NASH)など慢性炎症が発癌を促進する。本研究で慢性炎症と発癌を関連づける分子機構を究明した。IBD、colitis-associated cancer (CAC)の大腸組織、および肝癌組織を用いた。Heat shock protein A4 (HSPA4), Cold-inducible RNA-binding protein (Cirp), RNA-binding motif 3 (RBM3)欠損マウス、ガンキリン組織特異的欠損マウスと大腸および肝発癌マウスモデルを使用した。難治化したIBDの大腸粘膜においてストレス応答蛋白HSPA4, Cirp, RBM3、癌遺伝子ガンキリンの発現が亢進していた。HSPA4, Cirpは炎症細胞においてアポトーシス制御蛋白の発現を制御し炎症を増幅させ、RBM3は幹細胞マーカーR-spondinの発現を亢進させ上皮細胞の増殖を促進させる。ガンキリンは炎症細胞においてSrc homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) に結合しSTAT3を活性化し炎症を増幅する。このような腫瘍微小環境での炎症反応がERKの活性化や幹細胞の増殖を介して発癌を促進する。慢性炎症に対するストレス応答が発癌を促進する。また腫瘍微小環境において癌遺伝子ガンキリンはSTAT3, ERKの活性化を制御し発癌や治療抵抗性に関与している。これらの分子は消化器癌の発生や治療抵抗性リスクを予測するバイオマーカーであり、新規治療の標的となる可能性がある。

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: 8 Pages: 24762-24776
  • DOI: 10.18632/oncotarget.14983.
  • 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 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 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 Pages: 印刷中
  • DOI: 10.4049/jimmunol.1700060
  • Peer Reviewed
• [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 Pages: 印刷中
  • 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 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 pancreatitis. (2016)
  • Author(s): Watanabe T, Sadakane Y, Yagama N, Sakurai T, Ezoe H, Kudo M, Chiba T, Strober W
  • Journal Title: Mucosal Immunol Volume: 9 Pages: 1234-49.
  • DOI: 10.1038/mi.2015.144
  • Peer Reviewed
• [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）
  • Year and Date: 2016-11-03 – 2016-11-03
  • 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）
  • Year and Date: 2016-10-06 – 2016-10-06
• [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.
  • Year and Date: 2016-05-22 – 2016-05-22
  • 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）
  • Year and Date: 2016-05-13 – 2016-05-13
  • Int'l Joint Research
• [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）
  • Year and Date: 2016-04-22 – 2016-04-22
• [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
  • Year and Date: 2016-04-16 – 2016-04-16
  • Int'l Joint Research / Invited
• [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
  • Year and Date: 2016-04-15 – 2016-04-15
  • Int'l Joint Research / Invited