CD133 dependent signals and microRNAs in cancer stem cells

• Project/Area Number: 26462069
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kagoshima University
• Principal Investigator: MATSUBARA Shyuichiro 鹿児島大学, 医用ミニブタ・先端医療開発研究センター, 准教授 (60199841)
• Co-Investigator(Kenkyū-buntansha): 高尾 尊身 鹿児島大学, 医歯学総合研究科, 客員研究員 (80171411)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: CD133 / 癌幹細胞 / 膵臓癌 / マイクロRNA / 上皮間葉転換 (EMT) / Slug / HIF-1 / miR-30 / microRNA / HIF-1alpha / EMT / mTOR複合体 / シグナル伝達 / 膵癌幹細胞 / mTOR / Hedgehog / miRNA

Outline of Final Research Achievements

The molecular function of CD133 in the maintenance of cancer stem cells has not been elucidated. The CD133+ population of Capan-1 pancreatic cancer cell line exhibits cancer stem cell (CSC)-like properties. We established a CD133+ cell-rich subline from Capan-1 cells. Using this subline and the CD133 knocked down cells, we have shown that CD133 facilitates epithelial-mesenchymal transition (EMT) in pancreatic cancer cells. The protein level of EMT regulating transcription factor Slug and the miR-30 family of microRNA level are increased in CD133+ cells, and the expression of these factors can enhance mesenchymal phenotype. In addition, the protein level of HIF-1alpha, which plays a major role in cancer cell survival and aggressiveness in hypoxia, increases in CD133+ cells and may enhance the mesenchymal phenotype.

Research Products

• [Journal Article] Efficient elimination of pancreatic cancer stem cells by Hedgehog/GLI inhibitor GANT61 in combination with mTOR inhibition. (2016)
  • Author(s): Miyazaki Y, Matsubara S, Qiang Ding, Tsukasa K, Yoshimitsu M, Kosai K, Takao S.
  • Journal Title: Molecular Cancer Volume: 10 Issue: 1 Pages: 49-49
  • DOI: 10.1186/s12943-016-0534-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CD133 Modulate HIF-1α Expression under Hypoxia in EMT Phenotype Pancreatic Cancer Stem-Like Cells. (2016)
  • Author(s): Maeda K, Ding Q, Yoshimitsu M, Kuwahata T, Miyazaki Y, Tsukasa K, Hayashi T, Shinchi H, Natsugoe S, Takao S.
  • Journal Title: Int J Mol Sci. Volume: 17 Issue: 7 Pages: 1025-1025
  • DOI: 10.3390/ijms17071025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] miR-30 family promotes migratory and invasive abilities in CD133+ pancreatic cancer stem-like cells. (2016)
  • Author(s): Tsukasa K, Ding Q, Miyazaki 1, Matsubara S, Natsugoe S, Takao S
  • Journal Title: Hum Cell Volume: 28 Issue: 3 Pages: 1-8
  • DOI: 10.1007/s13577-016-0137-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] EMT inducing signals in CD133+ pancreatic cancer cells (2017)
  • Author(s): Matsubara S, Tsukasa K, Maeda K, Ding Q, Miyazaki Y, Obara T, Matsuyama T, Takao S.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] CD133陽性膵癌幹細胞様細胞においてmiR-30 familyは遊走と浸潤を促進する. (2017)
  • Author(s): 政 幸一郎、丁 強、宮崎 優美、松原 修一郎、上野 祥子、小原 徹、松山 隆美、高尾 尊身
  • Organizer: 第35回 日本ヒト細胞学会学術集会
• [Presentation] mTOR複合体1(mTORC1) および2(mTORC2)はCD133陽性膵癌細胞の幹細胞様性質に関与する. (2017)
  • Author(s): 松原 修一郎、政 幸一郎、宮崎 優美、小原 徹、松山 隆美、高尾 尊身
  • Organizer: 第35回 日本ヒト細胞学会学術集会
• [Presentation] 低酸素環境下におけるEMT形質を有する膵癌幹細胞様性質を持つ細胞においてCD133はHIF-1alphaの発現に関与する. (2017)
  • Author(s): 前田 幸喜、丁 強、吉満 誠、桑畑 大作、宮崎 優美、政 幸一郎、林 知美、新地 洋之、夏越 祥次、高尾 尊身
  • Organizer: 第35回 日本ヒト細胞学会学術集会
• [Presentation] mTOR複合体1(mTORC1) および2(mTORC2)はCD133陽性膵癌細胞の幹細胞様性質維持に異なる作用をもつ. (2017)
  • Author(s): 松原 修一郎、政 幸一郎、小原 徹、松山 隆美、高尾 尊身
  • Organizer: 2017年度生命科学系学会合同年次大会 (ConBio2017)
• [Presentation] Hedgehog/GLI and mTOR signals in pancreatic cancer stem cells (2016)
  • Author(s): Matsubara, S., Miyazaki, Y., Tsukasa, K., Obara, T., Matsuyama, T., Takao, S.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜 (神奈川県横浜市)
  • Year and Date: 2016-10-06
• [Presentation] CD133陽性膵癌幹細胞様細胞におけるmiR-30 famiｌyの機能 The role of miR30 family in pancreatic cancer stem-like cells (2016)
  • Author(s): 政 幸一郎、丁 強、宮崎 優美、松原 修一郎、上野 祥子、小原 徹、松山 隆美、高尾 尊身
  • Organizer: 第5回 膵勉強会
  • Place of Presentation: ホテルセントコスモ (鹿児島県・鹿児島市)
  • Year and Date: 2016-02-20
• [Presentation] 膵癌幹細胞の維持自己複製におけるmTORおよびHedgehogシグナルの機能 mTOR and Hedgehog signaling in pancreatic cancer stem cells (2015)
  • Author(s): 松原 修一郎、宮崎 優美、政 幸一郎、上野 祥子、小原 徹、松山 隆美、高尾 尊身
  • Organizer: BMB2015
  • Place of Presentation: 神戸国際展示場 (兵庫県・神戸市)
  • Year and Date: 2015-12-03
• [Presentation] The influence of miR-30 family to migration of a pancreatic cancer cell line, Capan-1 (2015)
  • Author(s): Tsukasa K, Miyazaki Y, Ueno S, Obara T, Matsubara S, Yoshimitsu M, Matsuyama T,Takao S
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場 (愛知県・名古屋市)
  • Year and Date: 2015-10-10
• [Presentation] CD133+ pancreatic cancer cells promote peritumonal fibrosis (2015)
  • Author(s): Miyazaki Y, Yoshimitsu M, Tsukasa K, Matsubara S, Obara T, Matsuyama T,Takao S
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場 (愛知県・名古屋市)
  • Year and Date: 2015-10-09
• [Presentation] Significant signaling in KRAS downstream cascade maintaining the stem-like property of pancreatic cancer cells. (2015)
  • Author(s): Matsubara S, Miyazaki Y, Tsukasa K, Obara T, Ueno S, Matsuyama T,Takao S
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場 (愛知県・名古屋市)
  • Year and Date: 2015-10-08
• [Presentation] Slug contributes to gemcitabine resistance through epithelial-mesenchymal transition in CD133(+) pancreatic cancer cells. (2015)
  • Author(s): Tsukasa K, Ding Q, Yoshimitsu M, Miyazaki Y, Matsubara S, Ueno S, Obara T, Matsuyama T,Takao S
  • Organizer: 第32回日本ヒト細胞学会学術集会
  • Place of Presentation: ホテルスカイタワー (宮崎県・宮崎市)
  • Year and Date: 2015-08-22
• [Presentation] 膵癌幹細胞とKRAS- mTOR経路 (2015)
  • Author(s): 松原 修一郎、政 幸一郎、宮崎 優美、小原 徹、高尾 尊身
  • Organizer: 第4回 膵勉強会
  • Place of Presentation: ブルーウェーブイン鹿児島 (鹿児島県鹿児島市)
  • Year and Date: 2015-03-07
• [Presentation] Not only mTORC1 but also mTORC2 are involved in the function to maintain stem-like property of pancreatic cancer cells. (2014)
  • Author(s): Matsubara S, Miyazaki Y, Tsukasa K, Obara T, Ueno S, Takao S
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜 (神奈川県横浜市)
  • Year and Date: 2014-09-25
• [Presentation] The role of miR-30a in the highly migratory pancreatic cancer cell line (2014)
  • Author(s): Tsukasa K, Matsubara S, Miyazaki Y, Obara T, Ueno S, Takao S
  • Organizer: 第73回日本癌学会学術総会 (横浜)
  • Place of Presentation: パシフィコ横浜 (神奈川県横浜市)
  • Year and Date: 2014-09-25