Molecular link between stress response and cancer and its clinical implication

• Project/Area Number: 17K09396
• 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)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 炎症性腸疾患 / ストレス応答 / 発癌 / HSP27 / 癌

Outline of Final Research Achievements

Stress responses to chronic inflammation promote the development of colorectal and liver cancer. Using knock-out mice, we clarified the role of Heat shock protein (HSP) 27 for tumorigenesis in the liver and colon. HSP27 is involved in the pathogenesis of liver and colorectal cancer. Gankyrin (GK) is an oncoprotein which regulates inflammatory responses and its inhibition is considered as a possible anti-inflammatory therapy for inflammatory bowel disease (IBD). Unexpectedly, GK-deficiency in the upper small bowel augmented inflammatory activity. Examination of human samples have confirmed that the reduction of GK expression in the small bowel is associated with colonic involvement in human Crohn’s disease. Through the sequencing of bacterial 16S rRNA gene amplicons, bacteria potentially deleterious to intestinal homeostasis were identified. These results provide important insights into the pathogenesis of IBD.

Academic Significance and Societal Importance of the Research Achievements

大腸上皮細胞および肝実質細胞でのHSP27の機能を解明し、新しい治療およびバイオマーカーの標的分子としての有用性が明らかとなった。大腸粘膜におけるHSP27の発現量は発癌リスクの予測に有用である。またWhole transcriptome解析により、炎症性腸疾患関連大腸癌の再発と相関する遺伝子セットを同定した。本研究の成果は大腸癌サーベイランスの効率化につながる。次世代シークエンサーを用いた解析により、TNF阻害薬の治療効果を予測する遺伝子セットおよび腸内細菌叢を同定した。炎症性疾患および癌領域における個別医療の実現に向けて、更なるデータの蓄積を行っていく。

Research Products

• [Journal Article] The Efficacy of Sonazoid-enhanced Ultrasonography in Decision-making for Liver Abscess Treatment (2020)
  • Author(s): Morita M, Ogawa C, Omura A, Noda T, Kubo A, Matsunaka T, Tamaki H, Shibatoge M, Seno H, Minami Y, Ueshima K, Sakurai T, Nishida N, Kudo M.
  • Journal Title: Internal Medicine Volume: 59 Issue: 4 Pages: 471-477
  • DOI: 10.2169/internalmedicine.2510-18
  • NAID: 130007798491
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-02-15
  • Peer Reviewed / Open Access
• [Journal Article] Deficiency of Gankyrin in the small intestine is associated with augmented colitis accompanied by altered bacterial composition of intestinal microbiota. (2020)
  • Author(s): *Sakurai T, Nishiyama H, Nagai T, Goto S, Ogata H, Kudo M.
  • Journal Title: BMC Gastroenterol. Volume: 15;20 Issue: 1 Pages: 12-26
  • DOI: 10.1186/s12876-019-1156-0
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of a modified double-guidewire technique using an uneven double lumen cannula (uneven method) in patients with surgically altered gastrointestinal anatomy (with video). (2020)
  • Author(s): Takenaka M, Minaga K, Kamata K, Yamao K, Yoshikawa T, Ishikawa R, Okamoto A, Yamazaki T, Nakai A, Omoto S, Komeda Y, Sakurai T, Watanabe T, Nishida N, Chiba Y, Kwon CI, Jeong S, Lee TH, Kudo M.
  • Journal Title: Surg Endosc. Volume: 34 Issue: 3 Pages: 1432-1441
  • DOI: 10.1007/s00464-019-07228-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Usefulness of Ustekinumab for Treating a Case of Myelodysplastic Syndrome-associated Inflammatory Bowel Disease (2019)
  • Author(s): Kono M, *Sakurai T, Okamoto K, Nagai T, Komeda Y, Kashida H, Minaga K, Kamata K, Takenaka M, Hagiwara S, Watanabe T, Nishida N, Enoki E, Inoue H, Matsumura I, Kudo M.
  • Journal Title: Internal Medicine Volume: 58 Issue: 14 Pages: 2029-2033
  • DOI: 10.2169/internalmedicine.2495-18
  • NAID: 130007679524
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-07-15
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Safety and Efficacy of Secondary Prophylactic Pegylated G-CSF in Advanced Pancreatic Cancer Patients Treated with mFOLFIRINOX: A Single-center Retrospective Study (2019)
  • Author(s): Yamao K, Takenaka M, Yoshikawa T, Ishikawa R, Okamoto A, Yamazaki T, Nakai A, Omoto S, Kamata K, Minaga K, Hagiwara S, Sakurai T, Nishida N, Chiba Y, Watanabe T, Kudo M.
  • Journal Title: Internal Medicine Volume: 58 Issue: 14 Pages: 1993-2002
  • DOI: 10.2169/internalmedicine.2234-18
  • NAID: 130007679534
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-07-15
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and Safety of Chemotherapy Following Anti-PD-1 Antibody Therapy for Gastric Cancer: A Case of Sclerosing Cholangitis (2019)
  • Author(s): Kono M, Sakurai T, Okamoto K, Masaki S, Nagai T, Komeda Y, Kamata K, Minaga K, Yamao K, Takenaka M, Watanabe T, Nishida N, Kudo M
  • Journal Title: Internal Medicine Volume: 58 Issue: 9 Pages: 1263-1266
  • DOI: 10.2169/internalmedicine.1981-18
  • NAID: 130007641397
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-05-01
  • Peer Reviewed / Open Access
• [Journal Article] Lenvatinib as an Initial Treatment in Patients with Intermediate-Stage Hepatocellular Carcinoma Beyond Up-To-Seven Criteria and Child-Pugh A Liver Function: A Proof-Of-Concept Study. (2019)
  • Author(s): Kudo M, Ueshima K, Chan S, Minami T, Chishina H, Aoki T, Takita M, Hagiwara S, Minami Y, Ida H, Takenaka M, Sakurai T, Watanabe T, Morita M, Ogawa C, Wada Y, Ikeda M, Ishii H, Izumi N, Nishida N.
  • Journal Title: Cancers (Basel) Volume: 11 Issue: 8 Pages: 1084-1084
  • DOI: 10.3390/cancers11081084
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of Baseline ALBI Grade on the Outcomes of Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Study. (2019)
  • Author(s): Ueshima K, Nishida N, Hagiwara S, Aoki T, Minami T, Chishina H, Takita M, Minami Y, Ida H, Takenaka M, Sakurai T, Watanabe T, Morita M, Ogawa C, Hiraoka A, Johnson P, Kudo M.
  • Journal Title: Cancers (Basel) Volume: 11 Issue: 7 Pages: 952-952
  • DOI: 10.3390/cancers11070952
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RICK/RIP2 is a NOD2-independent nodal point of gut inflammation (2019)
  • Author(s): Watanabe Tomohiro、Minaga Kosuke、Kamata Ken、Sakurai Toshiharu、Komeda Yoriaki、Nagai Tomoyuki、Kitani Atsushi、Tajima Masaki、Fuss Ivan J、Kudo Masatoshi、Strober Warren
  • Journal Title: International Immunology Volume: 31 Issue: 10 Pages: 669-683
  • DOI: 10.1093/intimm/dxz045
  • Peer Reviewed / Open Access
• [Journal Article] Contrast-enhanced harmonic endoscopic ultrasonography for evaluating the response to chemotherapy in pancreatic cancer. (2019)
  • Author(s): Tanaka H, Kamata K, Takenaka M, Yoshikawa T, Ishikawa R, Okamoto A, Yamazaki T, Nakai A, Omoto S, Minaga K, Yamao K, Sakurai T, Watanabe T, Nishida N, Chiba Y, Kitano M, Kudo M.
  • Journal Title: Dig Liver Dis. Volume: 51 Issue: 8 Pages: 1130-1134
  • DOI: 10.1016/j.dld.2019.03.015
  • Peer Reviewed / Open Access
• [Journal Article] Risk factors for local recurrence and appropriate surveillance interval after endoscopic resection. (2019)
  • Author(s): Komeda Y, Watanabe T, Sakurai T, Kono M, Okamoto K, Nagai T, Takenaka M, Hagiwara S, Matsui S, Nishida N, Tsuji N, Kashida H, Kudo M.
  • Journal Title: World J Gastroenterol Volume: 25 Issue: 12 Pages: 1502-1512
  • DOI: 10.3748/wjg.v25.i12.1502
  • Peer Reviewed / Open Access
• [Journal Article] Gankyrin Contributes to Tumorigenesis and Chemoresistance in Sporadic Colorectal Cancer. (2018)
  • Author(s): Sakurai T, Komeda Y, Nagai T, Kamata K, Minaga K, Yamao K, Takenaka M, Hagiwara S, Watanabe T, Nishida N, Kashida H, Nakagawa K, Kudo M.
  • Journal Title: Digestion. Volume: 4 Issue: 3 Pages: 1-9
  • DOI: 10.1159/000494969
  • Peer Reviewed / Open Access
• [Journal Article] Molecular Scoring of Hepatocellular Carcinoma for Predicting Metastatic Recurrence and Requirements of Systemic Chemotherapy. (2018)
  • Author(s): Nishida N, Nishimura T, Kaido T, Minaga K, Yamao K, Kamata K, Takenaka M, Ida H, Hagiwara S, Minami Y, Sakurai T, Watanabe T, Kudo M.
  • Journal Title: Cancers (Basel) Volume: 29 Issue: 10 Pages: 10-10
  • DOI: 10.3390/cancers10100367
  • Peer Reviewed / Open Access
• [Journal Article] Outcomes of endoscopic biliary drainage in pancreatic cancer patients with an indwelling gastroduodenal stent: a multicenter cohort study in West Japan. (2018)
  • Author(s): Yamao K, Kitano M, Takenaka M, Minaga K, Sakurai T, Watanabe T, Kayahara T, Yoshikawa T, Yamashita Y, Asada M, Okabe Y, Hanada K, Chiba Y, Kudo M.
  • Journal Title: Gastrointest Endosc Volume: 88 Issue: 1 Pages: 66-75
  • DOI: 10.1016/j.gie.2018.01.021
  • Peer Reviewed / Open Access
• [Journal Article] Value of additional endoscopic ultrasonography for surveillance after surgical removal of intraductal papillary mucinous neoplasms. (2018)
  • Author(s): Kamata K, Takenaka M, Minaga K, Omoto S, Miyata T, Yamao K, Imai H, Nakai A, Tanaka H, Chiba Y, Watanabe T, Sakurai T, Nishida N, Chikugo T, Matsumoto I, Takeyama Y, Kitano M, Kudo M.
  • Journal Title: Dig Endosc Volume: 印刷中 Issue: 5 Pages: 659-666
  • DOI: 10.1111/den.13176
  • NAID: 130007635776
  • Peer Reviewed / Open Access
• [Journal Article] Dysbiosis-Associated Polyposis of the Colon-Cap Polyposis. (2018)
  • Author(s): Okamoto K, Watanabe T, Komeda Y, Okamoto A, Minaga K, Kamata K, Yamao K, Takenaka M, Hagiwara S, Sakurai T, Tanaka T, Sakamoto H, Fujimoto K, Nishida N, Kudo M.
  • Journal Title: Front Immunol. Volume: 9 Pages: 918-918
  • DOI: 10.3389/fimmu.2018.00918
  • Peer Reviewed / Open Access
• [Journal Article] Supplementation of pancreatic digestive enzymes alters the composition of intestinal microbiota in mice. (2018)
  • Author(s): Nishiyama H, Nagai T, Kudo M, Okazaki Y, Azuma Y, Watanabe T, Goto S, Ogata H, Sakurai T.
  • Journal Title: Biochem Biophys Res Commun Volume: 495 Issue: 1 Pages: 273-279
  • DOI: 10.1016/j.bbrc.2017.10.130
  • NAID: 120006377721
  • Peer Reviewed / Open Access
• [Journal Article] Impact of avascular areas, as measured by contrast-enhanced harmonic EUS, on the accuracy of FNA for pancreatic adenocarcinoma. (2018)
  • Author(s): Kamata K, Takenaka M, Omoto S, Miyata T, Minaga K, Yamao K, Imai H, Sakurai T, Nishida N, Chikugo T, Chiba Y, Matsumoto I, Takeyama Y, Kudo M.
  • Journal Title: Gastrointest Endosc Volume: 87 Issue: 1 Pages: 158-163
  • DOI: 10.1016/j.gie.2017.05.052
  • Peer Reviewed / Open Access
• [Journal Article] Induction of Complete Remission by Azacitidine in a Patient with Myelodysplastic Syndrome-Associated Inflammatory Bowel Disease. (2018)
  • Author(s): Kono M, Komeda Y, Sakurai T, Okamoto A, Minaga K, Kamata K, Hagiwara S, Inoue H, Enoki E, Matsumura I, Watanabe T, Kudo M.
  • Journal Title: J Crohns Colitis Volume: 12 Issue: 4 Pages: 499-502
  • DOI: 10.1093/ecco-jcc/jjx170
  • Peer Reviewed / Open Access
• [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] Prophylactic Suturing Closure Is Recommended after Endoscopic Treatment of Colorectal Tumors in Patients with Antiplatelet/Anticoagulant Therapy. (2017)
  • Author(s): Sakurai T, Adachi T, Kono M, Arizumi T, Kamata K, Minaga K, Yamao K, Komeda Y, Takenaka M, Hagiwara S, Watanabe T, Nishida N, Kashida H, Kudo M
  • Journal Title: Oncology Volume: ９３ Issue: Suppl. 1 Pages: 27-29
  • DOI: 10.1159/000481226
  • Peer Reviewed / Open Access
• [Journal Article] Gankyrin induces STAT3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma. (2017)
  • Author(s): Sakurai T, Yada N, Hagiwara S, Arizumi T, Minaga K, Kamata K, Takenaka M, Minami Y, Watanabe T, Nishida N, Kudo M.
  • Journal Title: Cancer Sci. Volume: １０８ Issue: 10 Pages: 1996-2003
  • DOI: 10.1111/cas.13341
  • Peer Reviewed / Open Access
• [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: Inflamm Bowel Dis. Volume: 23 Issue: 1 Pages: 57-65
  • DOI: 10.1097/mib.0000000000000968
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Contribution of C1485T mutation in the HBx gene to human and murine hepatocarcinogenesis (2017)
  • Author(s): Hagiwara Satoru、Nishida Naoshi、Park Ah-Mee、Komeda Yoriaki、Sakurai Toshiharu、Watanabe Tomohiro、Kudo Masatoshi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 10440-10440
  • DOI: 10.1038/s41598-017-10570-0
  • Peer Reviewed / Open Access
• [Journal Article] A Case of Type II Enteropathy-Associated T-Cell Lymphoma in a Patient With Ulcerative Colitis. (2017)
  • Author(s): Komeda Y, Kashida H, Sakurai T, Kono M, Nagai T, Asakuma Y, Hagiwara S, Matsui S, Watanabe T, Chikugo T, Kudo M.
  • Journal Title: Am J Gastroenterol Volume: 112 Issue: 6 Pages: 833-833
  • DOI: 10.1038/ajg.2017.56
  • 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
• [Presentation] 小腸におけるガンキリンは腸内細菌叢および大腸炎に影響する (2019)
  • Author(s): 永井知行、櫻井俊治、西山拓輝、緒方博之、工藤正俊
  • Organizer: 第56回日本消化器免疫学会総会 シンポジウム
• [Presentation] 胃癌実臨床における免疫チェックポイント阻害薬の有効性と安全性 (2019)
  • Author(s): 岡元寿樹、櫻井俊治、今野元博
  • Organizer: 第105回日本消化器病学会総会シンポジウム
• [Presentation] 腸内細菌叢とがん (2019)
  • Author(s): 櫻井俊治、工藤正俊
  • Organizer: 第23回日本がん分子標的治療学会シンポジウム
  • Invited
• [Presentation] 大腸ポリープ識別のためのAI（人工知能）を用いた拡大内視鏡実施下CNNシステムによるコンピューター自動診断 (2019)
  • Author(s): 米田頼晃、櫻井俊治、工藤正俊
  • Organizer: 第97回日本消化器内視鏡学会総会シンポジウム
• [Presentation] ヒマシ油ブースター使用による大腸カプセル内視鏡検査の前処置軽減の取り組み:pilot study (2019)
  • Author(s): 米田頼晃、櫻井俊治、工藤正俊
  • Organizer: 第97回日本消化器内視鏡学会総会パネルディスカッション
• [Presentation] 胃癌における免疫チェックポイント阻害剤の有効性と副作用 (2019)
  • Author(s): 河野匡志、櫻井俊治、今野元博、工藤正俊
  • Organizer: 第92回日本胃癌学会総会
• [Presentation] Gankyrin in the small intestine controls colonic microbiota and attenuates colitis. (2018)
  • Author(s): Sakurai T, Nagai T, Kudo M
  • Organizer: 第26回日本消化器関連学会週間 （JDDW2018)
• [Presentation] Stress response protein RBM3 promotes the development of colitis-associated cancer. (2018)
  • Author(s): 櫻井俊治、工藤正俊
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Gankyrin in the small intestine controls colonic microbiota and attenuates colitis (2018)
  • Author(s): 櫻井俊治、坂井和子、西尾和人、工藤正俊
  • Organizer: 化学コミュニケーションのフロンティア 第1回国際シンポジウム
  • Int'l Joint Research
• [Presentation] Surveillance colonoscopy for ulcerative colitis; Up-to-date procedure and therapeutic strategy (2017)
  • Author(s): Sakurai T, Sakai K, Kashida H, Nishio K, Kudo M
  • Organizer: Japan Digestive Disease Week 2017
• [Presentation] STAT3を標的とした分子標的薬の治療効果予測 (2017)
  • Author(s): 櫻井俊治 工藤正俊
  • Organizer: 第15回 日本臨床腫瘍学会学術集会
• [Presentation] STAT3を標的とした分子標的薬の治療効果予測 (2017)
  • Author(s): 櫻井俊治 工藤正俊
  • Organizer: 第103回 日本消化器病学会総会
• [Book] Human Cell Transformation (2019)
  • Author(s): Jun Fujita, Toshiharu Sakurai
  • Total Pages: 244
  • Publisher: Springer