The regulation of colon cancer stem cell by QKI5

• Project/Area Number: 17K16555
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kobe University
• Principal Investigator: MUKOHYAMA JUNKO 神戸大学, 医学研究科, 医学研究員 (70734987)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 大腸癌 / マイクロRNA / miR-221 / RNA結合蛋白 / QKI / 癌幹細胞 / シークエンス解析 / QKI5

Outline of Final Research Achievements

In this study, we identified miR-221 was highly expressed in cancer stem cell population in colon cancer tissue. High levels of miR-221 expression reduced survival in CRC patients. miR-221 enhanced organoid-forming capacity of both conventional CRC cell lines and patient-derived xenografts (PDXs) in vitro. Importantly, constitutive downregulation of miR-221 suppressed organoid-forming capacity in vitro and substantially reduced the tumorigenic capacity of CSC populations from PDX lines in vivo. Finally, QKI-5, was identified as a functional targets of miR-221. As expected, overexpression of QKI-5 suppressed organoid-forming capacity in vitro and tumorigenic capacity of CRC PDX cells in vivo. Our study reveals a mechanistic link between miR-221 and QKI, and highlights their key role in regulating CSC properties in human colorectal cancer.

Academic Significance and Societal Importance of the Research Achievements

本研究では、大腸癌組織中の大腸癌幹細胞のマイクロRNAプロファイルを世界に先駆け明らかにした。また、大腸癌幹細胞でマイクロRNA-221の発現が選択的に上昇していることを発見し、マイクロRNA-221が大腸癌の幹細胞性を制御する機能をもつことを解明した。さらに、マイクロRNA-221の標的遺伝子としてRNA結合蛋白質QKI-5を同定した。本研究の成果は、マイクロRNA-221の抑制による癌幹細胞を標的とした治療薬の開発への応用が期待できる。

Research Products

• [Int'l Joint Research] コロンビア大学(米国)
• [Int'l Joint Research] コロンビア大学(米国)
• [Journal Article] miR-221 Targets QKI to Enhance the Tumorigenic Capacity of Human Colorectal Cancer Stem Cells. (2019)
  • Author(s): Mukohyama J, Isobe T, Hu Q, Hayashi T, Watanabe T, Maeda M, Yanagi H, Qian X, Yamashita K, Minami H, Mimori K, Sahoo D, Kakeji Y, Suzuki A, Dalerba P, Shimono Y.
  • Journal Title: Cancer Research Volume: 79 Issue: 20 Pages: 5151-5158
  • DOI: 10.1158/0008-5472.can-18-3544
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Recent advances of neoadjuvant chemoradiotherapy in rectal cancer: Future treatment perspectives (2018)
  • Author(s): Yamashita Kimihiro、Matsuda Takeru、Hasegawa Hiroshi、Mukohyama Junko、Arimoto Akira、Tanaka Tomoko、Yamamoto Masashi、Matsuda Yoshiko、Kanaji Shingo、Nakamura Tetsu、Sumi Yasuo、Suzuki Satoshi、Kakeji Yoshihiro
  • Journal Title: Annals of Gastroenterological Surgery Volume: 3 Issue: 1 Pages: 24-33
  • DOI: 10.1002/ags3.12213
  • Peer Reviewed
• [Journal Article] Roles of microRNAs and RNA-binding proteins in the regulation of colorectal cancer stem cells. (2017)
  • Author(s): Mukohyama J, Shimono Y, Minami H, Kakeji Y, Suzuki A.
  • Journal Title: CANCER Volume: 9(10) Issue: 10 Pages: 143-143
  • DOI: 10.3390/cancers9100143
  • NAID: 120006373809
  • Peer Reviewed / Open Access
• [Journal Article] Discordance of MCM7 mRNA and Its Intronic MicroRNA Levels under Hypoxia (2017)
  • Author(s): Hiroki Kondo, Yohei Shimono, Junko Mukohyama, Yasuteru Tanaka, Naoki Shibuya, Hironobu Minami, Yoshihiro Kakeji, Akira Suzuki
  • Journal Title: Anticancer Research Volume: 37 Pages: 3885-3890
  • Peer Reviewed
• [Journal Article] MicroRNA Regulation of Cancer Stem Cells at the Primary and Metastatic Sites (2017)
  • Author(s): 下野 洋平, 渋谷 尚樹, 向山 順子, 西村 建徳, 後藤 典子, 南 博信, 掛地 吉弘, 鈴木 聡
  • Journal Title: Cytometry Research Volume: 27 Issue: 1 Pages: 33-39
  • DOI: 10.18947/cytometryresearch.27.1_33
  • NAID: 130006832441
  • ISSN: 0916-6920, 2424-0664
  • Peer Reviewed
• [Presentation] miR-221 enhances functional behaviors of cancer stem cells in human colorectal cancers. (2019)
  • Author(s): unko Mukohyama, Yohei Shimono, Taichi Isobe, Qingjiang Hu, Debashis Sahoo, Hironobu Minami, Koshi Mimori, Piero Dalerba, Yoshihiro Kakeji, Akira Suzuki.
  • Organizer: 11th AACR-JCA joint conference
  • Int'l Joint Research
• [Presentation] miR-221 enhances functional behaviors of cancer stem cells in human colorectal cancers (2019)
  • Author(s): Junko Mukohyama, Yohei Shimono, Piero Dalerba, Taichi Isobe, Qingjiang Hu, Debashis Sahoo, Hironobu Minami, Koshi Mimori, Yoshihiro Kakeji, Akira Suzuki
  • Organizer: 11th AACR-JCA joint conference
  • Int'l Joint Research
• [Presentation] Epigenetic regulation of colorectal cancer stem cells by the miR-221/QKI5 axis (2018)
  • Author(s): Junko Mukohyama, Yohei Shimono, Piero Dalerba, Taichi Isobe, Qingjiang Hu, Debashis Sahoo, Naoki Shibuya, Hironobu Minami, Koshi Mimori, Yoshihiro Kakeji, Akira Suzuki.
  • Organizer: AACR Annual Meeting
  • Int'l Joint Research
• [Presentation] Epigenetic regulation of colorectal cancer stem cells by the miR-221/QKI5 axis (2018)
  • Author(s): Junko Mukohyama, Yohei Shimono, Piero Dalerba, Taichi Isobe, Qingjiang Hu, Debashis Sahoo, Naoki Shibuya, Hironobu Minami, Koshi Mimori, Yoshihiro Kakeji, Akira Suzuki
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Detection of EBV BamHI W region in surgical cancer specimen is a useful method to evaluate the risk of lymphomagenesis in patient-derived tumor xenografts (2017)
  • Author(s): Junko Mukohyama, Dai Iwakiri, Yoh Zen, Toru Mukohara, Hironobu Minami, Yoshihiro Kakeji, Yohei Shimono
  • Organizer: ACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] MicroRNA-mediated upregulation of the WNT signaling activities in human breast cancer stem cells (2017)
  • Author(s): Yohei Shimono, Taichi Isobe, Andrei Turtoi, Junko Mukohyama, Toru Mukohara, Akira Suzuki, Vincent Castronovo, Hironobu Minami
  • Organizer: ACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] miR-221-QKI5 axis regulates tumorigenicity of human colorectal cancer stem cells (2017)
  • Author(s): Junko Mukohyama, Yohei Shimono, Taichi Isobe, Qingjiang Hu, Naoki Shibuya, Kimihiro Yamashita, Koshi Mimori, Hironobu Minami, Yoshihiro Kakeji, Akira Suzuki
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
• [Remarks] 大腸がんの「がん幹細胞」制御因子としてマイクロRNA-221を同定
  • URL: https://www.kobe-u.ac.jp/research_at_kobe/NEWS/news/2019_10_25_01.html