Clinical significance of sphingosine-1-phosphate and sphingosine kinase 1 in lymphatic spread of esophageal cancer

• Project/Area Number: 16K10491
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Niigata University
• Principal Investigator: Ichikawa Hiroshi 新潟大学, 医歯学系, 助教 (50721875)
• Co-Investigator(Kenkyū-buntansha): 永橋 昌幸 新潟大学, 医歯学総合病院, 研究准教授 (30743918) ; 若井 俊文 新潟大学, 医歯学系, 教授 (50372470) ; 羽入 隆晃 新潟大学, 医歯学総合病院, 助教 (50719705) ; 小杉 伸一 新潟大学, 医歯学総合病院, 特任教授 (90401736)
• Research Collaborator: MUNEOKA Yusuke ; NAKANO Masato ; TANAKA Kana ; SUDO Natsuru ; SAKIMURA Kenji ; ABE Manabu
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 食道癌 / リンパ行性進展 / スフィンゴシンキナーゼ1型 / スフィンゴシン-1-リン酸 / 食道扁平上皮癌 / 免疫組織化学染色 / pSphK1 / 免疫組織化学 / リンパ管侵襲 / 食道外科学 / 脂質メディエーター

Outline of Final Research Achievements

We evaluated pSphK1 and SphK1 expression in 92 surgically resected tumor tissues of esophageal cancer by the immunohistochemistry. Lymph node metastasis, lymphatic invasion and intramural metastasis were significantly associated with high expression of pSphK1. The 5-year overall survival rate of patients with pSphK1-high expression was significantly lower than that of patients with pSphK1-low expression. SphK1 expression was not associated with lymphatic spread and prognosis in patients with esophageal cancer. We provide the first evidence of the association between high expression of pSphK1 and both lymphatic spread and patient outcomes in esophageal cancer.

Academic Significance and Societal Importance of the Research Achievements

食道癌ではリンパ節転移が強力な予後因子であり、リンパ行性進展は最も重要な進展形式である。スフィンゴシン-1-リン酸（以下S1P）は細胞情報伝達物質として働く脂質メディエーターであり、S1P産生責任酵素であるスフィンゴシンキナーゼ1型が活性化されることで産生される。このS1Pシグナルは癌のリンパ行性進展に関わることが報告されているが、食道癌における役割は未解明である。本研究成果により、食道癌のリンパ行性進展にはS1Pシグナルが関与している可能性が示唆された。S1Pシグナルを阻害する薬剤が既に他の疾患で臨床応用されており、今後は同シグナルを標的とした新たな食道癌治療開発が期待される。

Research Products

• [Journal Article] Phospho-Sphingosine Kinase 1 Expression in Lymphatic Spread of Esophageal Squamous Cell Carcinoma (2019)
  • Author(s): Nemoto Mariko、Ichikawa Hiroshi、Nagahashi Masayuki、Hanyu Takaaki、Ishikawa Takashi、Kano Yosuke、Muneoka Yusuke、Wakai Toshifumi
  • Journal Title: Journal of Surgical Research Volume: 234 Pages: 123-131
  • DOI: 10.1016/j.jss.2018.09.012
  • Peer Reviewed
• [Journal Article] Hyperbilirubinemia predicts the infectious complications after esophagectomy for esophageal cancer (2019)
  • Author(s): Muneoka Yusuke、Ichikawa Hiroshi、Kosugi Shin-ichi、Hanyu Takaaki、Ishikawa Takashi、Kano Yosuke、Shimada Yoshifumi、Nagahashi Masayuki、Sakata Jun、Kobayashi Takashi、Kameyama Hitoshi、Akazawa Kohei、Wakai Toshifumi
  • Journal Title: Annals of Medicine and Surgery Volume: 39 Pages: 16-21
  • DOI: 10.1016/j.amsu.2019.02.004
  • Peer Reviewed
• [Journal Article] Surgical and long-term outcomes following oesophagectomy in oesophageal cancer patients with comorbidity (2016)
  • Author(s): Ichikawa H, Kosugi SI, Kanda T, Yajima K, Ishikawa T, Hanyu T, Muneoka Y, Otani T, Nagahashi M, Sakata J, Kobayashi T, Kameyama H, Wakai T
  • Journal Title: International Journal of Surgery Volume: 36 Pages: 212-218
  • DOI: 10.1016/j.ijsu.2016.10.041
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Prognostic significance of NQO1 expression in esophageal squamous cell carcinoma after preoperative chemotherapy with cisplatin and 5-fluorouracil followed by curative esophagectomy (2016)
  • Author(s): Ichikawa H, Kosugi S, Hirose Y, Matsuda Y, Ishikawa T, Hanyu T, Usui K, Muneoka Y, Nagahashi M, Sakata J, Kobayashi T, Kameyama H, Wakai T
  • Journal Title: International Journal of Clinical and Experimental Pathology Volume: 9 Pages: 7393-7401
  • Peer Reviewed
• [Journal Article] Low fat-containing elemental formula is effective for postoperative recovery and potentially useful for preventing chyle leak during postoperative early enteral nutrition after esophagectomy. (2016)
  • Author(s): Moro K, Koyama Y, Kosugi SI, Ishikawa T, Ichikawa H, Hanyu T, Miura K, Nagahashi M, Nakajima M, Tatsuda K, Tsuchida J, Toshikawa C, Ikarashi M, Shimada Y, Sakata J, Kobayashi T, Kameyama H, Wakai T
  • Journal Title: Clinical Nutrition Volume: 35 Issue: 6 Pages: 1423-1428
  • DOI: 10.1016/j.clnu.2016.03.018
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] The Significance of Phospho-Sphingosine Kinase 1 in the Lymphatic Spread of Esophageal Carcinoma (2018)
  • Author(s): Ichikawa H, Nagahashi M, Nemoto M, Hanyu T, Ishikawa T, Kano Y, Muneoka Hirose Y, Shimada Y, Sakata J, Kobayashi T, Kameyama H, Kazuaki T, Wakai T
  • Organizer: 13th Annual Academic Surgical Congress
  • Int'l Joint Research
• [Presentation] Sphingosine Kinase Type 1 and Type 2 Works Differently in Pancreatic Cancer (2018)
  • Author(s): Nakajima M, Yuza K, Tsuchida J, Hirose Y, Miura K, Ichikawa H, Shimada Y, Kobayashi T, Sakata J, Kameyama H, Abe M, Sakimura K, Wakai T, Nagahashi M
  • Organizer: 13th Annual Academic Surgical Congress
  • Int'l Joint Research
• [Presentation] High Levels of Sphingolipids in Human Pancreatic Cancer (2018)
  • Author(s): Yuza K, Nagahashi M, Hirose Y, Nakajima M, Miura K, Ichikawa H, Shimada Y, Sakata J, Kameyama H, Kobayashi T, Takabe K, Wakai T
  • Organizer: 13th Annual Academic Surgical Congress
  • Int'l Joint Research
• [Presentation] Human Biliary Tract Cancer Contains High Levels of S1P (2018)
  • Author(s): Hirose Y, Nagahashi M, Yuza K, Miura K, Sakata J, Kobayashi T, Ichikawa H, Shimada Y, Kameyama H, Takabe K, Wakai T
  • Organizer: 13th Annual Academic Surgical Congress
  • Int'l Joint Research
• [Presentation] Dysregulation of Sphingolipids in Human Hepatocellular Carcinoma (2018)
  • Author(s): Miura K, Nagahashi M, Hirose Y, Kobayashi T, Sakata J, Kameyama H, Shimada Y, Ichikawa H, Takabe K, Wakai T
  • Organizer: 13th Annual Academic Surgical Congress
  • Int'l Joint Research
• [Presentation] High Expression of Sphingosine Kinase 1 in Colitis-Associated Cancer (2018)
  • Author(s): Yuza K, Nagahashi M, Shimada Y, Nakano M, Tajima Y, Kameyama H, Nakajima M, Ichikawa H, Sakata J, Kobayashi T, Takabe K, Wakai T
  • Organizer: 13th Annual Academic Surgical Congress
  • Int'l Joint Research
• [Presentation] 食道扁平上皮癌リンパ行性進展におけるphospho-sphingosine kinase 1発現の意義 (2018)
  • Author(s): 市川 寛，根本 万理子，石川 卓，羽入 隆晃，角田 知行，須藤 翔，島田 能史，永橋 昌幸，坂田 純，小林 隆，亀山 仁史，若井 俊文
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] The Significance of Phospho-Sphingosine Kinase 1 in the Lymphatic Spread of Esophageal Carcinoma (2018)
  • Author(s): Hiroshi Ichikawa, Masayuki Nagahashi, Mariko Nemoto, Takaaki Hanyu, Takashi Ishikawa, Yosuke Kano, Yusuke Muneoka, Yoshifumi Shimada, Jun Sakata, Takashi Kobayashi, Hitoshi Kameyama, Toshifumi Wakai
  • Organizer: 13th Annual Academic Surgical Congress
  • Int'l Joint Research