Chromosomal dynamics and development of novel therapy in gastrointestinal tract cancer

• Project/Area Number: 25462024
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: Saeki Hiroshi 九州大学, 医学(系)研究科(研究院), 准教授 (80325448)
• Co-Investigator(Kenkyū-buntansha): MORITA MASARU 独立行政法人国立病院機構, (九州がんセンター臨床研究センター), 統括診療部長 (30294937) ; KITAO HIROYUKI 九州大学, 医学研究院, 准教授 (30368617) ; OKI EIJI 九州大学, 大学病院, 講師 (70380392)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 染色体不安定性 / 集学的治療 / 消化管癌 / 染色体分配機構 / 難治性消化管癌 / PAK / 食道癌 / 遺伝子プロファイル

Outline of Final Research Achievements

Temporal regulation of microtubule dynamics is essential for proper progression of mitosis and control of microtubule plus-end tracking proteins by phosphorylation is an essential component of this regulation. Aurora B and CDK1 phosphorylate microtubule end-binding protein 2 (EB2) at multiple sites within the amino terminus and a cluster of serine/threonine residues in the linker connecting the calponin homology and end-binding homology domains. EB2 phosphorylation, which is strictly associated with mitotic entry and progression, reduces the binding affinity of EB2 for microtubules. Expression of non-phosphorylatable EB2 induces stable kinetochore microtubule dynamics and delays formation of bipolar metaphase plates in a microtubule binding-dependent manner, and leads to aneuploidy even in unperturbed mitosis. Aurora B and CDK1 temporally regulate the binding affinity of EB2 for microtubules, ensuring kinetochore microtubule dynamics, proper mitotic progression and genome stability.

Research Products

• [Journal Article] Phosphorylation of EB2 by Aurora B and CDK1 ensures mitotic progression and genome stability. (2016)
  • Author(s): Iimori M, Watanabe S, Kiyonari S, Matsuoka K, Sakasai R, Saeki H, Oki E, Kitao H, Maehara Y:
  • Journal Title: Nature Communications Volume: [Epub ahead of print] Issue: 1 Pages: 11117-11117
  • DOI: 10.1038/ncomms11117
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic Significance of Postoperative Complications after Curative Resection for Patients with Esophageal Squamous Cell Carcinoma. (2016)
  • Author(s): Saeki H, Tsutsumi S, Tajiri H, Yukaya T, Tsutsumi R, Nishimura S, Nakaji Y, Kudou K, Akiyama S, Kasagi Y, Nakanishi R, Nakashima Y, Sugiyama M, Ohgaki K, Sonoda H, Oki E, Maehara Y:
  • Journal Title: Annals of Surgery Volume: [Epub ahead of print]
  • Peer Reviewed
• [Journal Article] Current status of and perspectives regarding neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. (2016)
  • Author(s): Saeki H, Nakashima Y, Zaitsu Y, Tsuda Y, Kasagi Y, Ando K, Imamura Y, Ohgaki K, Ito S, Kimura Y, Egashira A, Oki E, Morita M, Maehara Y:
  • Journal Title: Surgery Today Volume: 46 Pages: 261-7
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Peritoneal dissemination requires an Sp1-dependent CXCR4/CXCL12 signaling axis and extracellular matrix-directed spheroid formation. (2016)
  • Author(s): Kasagi Y, Harada Y, Morodomi Y, Iwai T, Saito S, Yoshida K, Oki E, Saeki H, Ohgaki K, Sugiyama M, Onimaru M, Maehara Y, Yonemitsu Y:
  • Journal Title: Cancer Research Volume: 76 Issue: 2 Pages: 347-57
  • DOI: 10.1158/0008-5472.can-15-1563
  • Peer Reviewed
• [Journal Article] Esophagectomy for superficial esophageal cancer after non-curative endoscopic resection. (2015)
  • Author(s): Saeki H, Watanabe M, Mine S, Shigaki H, Oya S, Ishiyama A, Tsuchida T, Fujisaki J, Baba H, Maehara Y, Sano T:
  • Journal Title: Journal of Gastroenterology Volume: 50 Pages: 406-13
  • Peer Reviewed
• [Journal Article] Current status of and perspectives regarding neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma (2015)
  • Author(s): Saeki H, Nakashima Y, Zaitsu Y, Tsuda Y, Kasagi Y, Ando K, Imamura Y, Ohgaki K, Ito S, Kimura Y, Egashira A, Oki E, Morita M, Maehara Y
  • Journal Title: Surg Today Volume: Mar 5. [Epub ahead of print] Issue: 3 Pages: 261-7
  • DOI: 10.1007/s00595-015-1144-0
  • Peer Reviewed / Open Access
• [Journal Article] Chromosomal instability associated with global DNA hypomethylation is associated with the initiation and progression of esophageal squamous cell carcinoma (2014)
  • Author(s): Kawano H, Saeki H, Kitao H, Tsuda Y, Otsu H, Ando K, Ito S, Egashira A, Oki E, Morita M, Oda Y, Maehara Y.
  • Journal Title: Annals of Surgical Oncology Volume: 4 Issue: S4 Pages: 696-702
  • DOI: 10.1245/s10434-014-3818-z
  • Peer Reviewed / Open Access
• [Presentation] 食道癌に対する術前治療の効果予測バイオマーカーとしてのRad51発現の意義 (2015)
  • Author(s): 佐伯浩司、中ノ子智徳、堤 亮介、西村 章、中司 悠、田尻裕匡、堤 智崇、由茅隆文、笠木勇太、杉山雅彦、中島雄一郎、園田英人、大垣吉平、沖 英次、前原喜彦
  • Organizer: 第53回日本癌治療学会
  • Place of Presentation: 京都
  • Year and Date: 2015-10-29
• [Presentation] 食道癌に対する腹臥位鏡視下食道切除術－両肺換気・気胸法によるリンパ節郭清の利点－ (2015)
  • Author(s): 佐伯浩司、中島雄一郎、堤 智崇、由茅隆文、田尻裕匡、堤 亮介、西村 章、中司 悠、工藤健介、笠木勇太、杉山雅彦、園田英人、大垣吉平、沖 英次、前原喜彦
  • Organizer: 第68回日本胸部外科学会定期学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2015-10-18
• [Presentation] cT因子からみたcStageII/III食道扁平上皮癌に対する術前化学放射線療法の意義と治療効果予測バイオマーカー (2015)
  • Author(s): 佐伯浩司、財津瑛子、津田康雄、笠木勇太、中島雄一郎、安藤幸滋、今村 裕、大垣吉平、沖 英次、前原喜彦
  • Organizer: 第70回日本消化器外科学会総会
  • Place of Presentation: 浜松
  • Year and Date: 2015-07-15
• [Presentation] 頸部食道癌に対する手術成績と臨床病理学的特徴 (2015)
  • Author(s): 佐伯浩司、堤 智崇、由茅隆文、田尻裕匡、中島雄一郎、安藤幸滋、今村 裕、大垣吉平、沖 英次、前原喜彦
  • Organizer: 第69回日本食道学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2015-07-03
• [Presentation] cT3/nearly T4食道癌に対する集学的治療戦略－治療効果と安全性の両立を目指して－ (2015)
  • Author(s): 佐伯浩司、工藤健介、堤 亮介、中司 悠、西村 章、秋山真吾、田尻裕匡、堤 智崇、由茅隆文、笠木勇太、財津瑛子、津田康雄、安藤幸滋、中島雄一郎、今村 裕、大垣吉平、沖 英次、前原喜彦
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-04-16
• [Presentation] 食道癌におけるグローバルDNA低メチル化と染色体不安定性 (2014)
  • Author(s): 佐伯浩司、河野浩幸、西村 章、堤 亮介、中司 悠、工藤健介、堤 智崇、由茅隆文、田尻裕匡、笠木勇太、津田康雄、財津瑛子、安藤幸滋、中島雄一郎、今村 裕、大垣吉平、沖 英次、北尾洋之、前原喜彦
  • Organizer: 第25回日本消化器癌発生学会総会/第8回国際消化器癌発生会議, シンポジウム
  • Place of Presentation: 福岡
  • Year and Date: 2014-11-13 – 2014-11-14
• [Presentation] Global DNA hypomethylation-mediated chromosomal instability is related to the initiation and progression of esophageal squamous cell carcinoma (2014)
  • Author(s): Kawano H, Saeki H, Kitao H, Tsuda Y, Otsu H, Ando K, Ito S, Egashira A, Oki E, Morita M, Maehara Y
  • Organizer: 2014 Annual meeting of American Society of Clinical Oncology (ASCO)
  • Place of Presentation: Chicago
  • Year and Date: 2014-05-30 – 2014-06-03
• [Presentation] 食道癌の発生・進展におけるグローバルDNA低メチル化の意義 (2014)
  • Author(s): 佐伯浩司、河野浩幸、前原喜彦
  • Organizer: 第100回日本消化器病学会総会, シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2014-04-23
• [Presentation] 食道癌の発生・進展におけるグローバルDNA低メチル化の意義
  • Author(s): 佐伯浩司
  • Organizer: 第100回日本消化器病学会
  • Place of Presentation: 東京国際フォーラム