The mechanisms of acquiring chemo-resistance and identification of therapeutic targets in colorectal cancer stem cells.

• Project/Area Number: 17K16571
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: IZUMI Daisuke 熊本大学, 医学部附属病院, 非常勤診療医師 (60594877)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 大腸癌幹細胞 / 抗癌剤耐性 / FBXW7 / c-Myc / Xenograft / 癌幹細胞 / LGR5 / 抗癌剤 / 抗がん剤耐性

Outline of Final Research Achievements

The cancer stem cell (CSC) paradigm suggests that tumors are organized hierarchically. We performed this study to elucidate the molecular mechanisms responsible for evading cell death in colorectal CSCs mediated by anticancer agents. During the cell cycle arrest caused by anticancer agents, c-Myc expression was substantially decreased in colorectal CSCs. The c-Myc expression alterations were mediated by upregulation of F-box/WD repeat-containing protein 7 (FBXW7). Differentiated CSCs treated with anticancer agents did not show upregulation of FBXW7 and were more sensitive to irinotecan (CPT-11), highlighting the potential CSC-specific nature of our data. The FBXW7 over-expression was further validated in resected liver metastatic sites in CRC patients after chemotherapy. In conclusion, our study revealed that a CSC-specific FBXW7-regulatory mechanism is strongly associated with resistance to chemotherapeutic agents.

Academic Significance and Societal Importance of the Research Achievements

今回の研究で大腸癌幹細胞特異的なFBXW7調整メカニズムは抗癌剤耐性に強くかかわっていることが分かった。このメカニズムをターゲットとすることで大腸癌幹細胞の新たな治療戦略に寄与することができる可能性がある。

Research Products

• [Journal Article] A genomewide transcriptomic approach identifies a novel gene expression signature for the detection of lymph node metastasis in patients with early stage gastric cancer (2019)
  • Author(s): Izumi Daisuke、Gao Feng、Toden Shusuke、Sonohara Fuminori、Kanda Mitsuro、Ishimoto Takatsugu、Kodera Yasuhiro、Wang Xin、Baba Hideo、Goel Ajay
  • Journal Title: EBioMedicine Volume: 41 Pages: 268-275
  • DOI: 10.1016/j.ebiom.2019.01.057
  • Peer Reviewed
• [Journal Article] Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression (2018)
  • Author(s): Eto T, Miyake K, Nosho K, Ohmuraya M, Imamura Y, Arima K, Kanno S, Fu L, Kiyozumi Y, Izumi D, Sugihara H, Hiyoshi Y, Miyamoto Y, Sawayama H, Iwatsuki M, Baba Y, Yoshida N, Furukawa T, Araki K, Baba H, Ishimoto T
  • Journal Title: The Journal of Pathology Volume: 245 Issue: 4 Pages: 445-455
  • DOI: 10.1002/path.5098
  • Peer Reviewed
• [Journal Article] Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas (2018)
  • Author(s): Arima Kota、Ohmuraya Masaki、Miyake Keisuke、Koiwa Mayu、Uchihara Tomoyuki、Izumi Daisuke、Gao Feng、Yonemura Atsuko、Bu Luke、Okabe Hirohisa、Imai Katsunori、Hashimoto Daisuke、Baba Yoshifumi、Chikamoto Akira、Yamashita Yo-ichi、Furukawa Toru、Araki Kimi、Baba Hideo、Ishimoto Takatsugu
  • Journal Title: Oncogene Volume: 38 Issue: 8 Pages: 1211-1224
  • DOI: 10.1038/s41388-018-0510-y
  • Peer Reviewed