Elucidation of the generation mechanism of cancer stem cells from circadian clock defective cells and development of strategy for overcoming of chemoresistance

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K21484
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: Kyushu University
• Principal Investigator: Koyanagi Satoru 九州大学, 薬学研究院, 教授 (60330932)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Keywords: 概日時計 / 時計遺伝子 / がん幹細胞 / 薬剤耐性

Outline of Final Research Achievements

Tumor tissue is composed of not only cancer cells, but also numerous non-cancer cells such as fibroblasts, epithelial cells, and various types of immune cells. Those tumor microenvironmental cells support tumor growth and resistance to chemotherapy. Some specific tumor cell populations present as cancer stem-like cells (CSCs) have a high malignant potential and resistance to chemotherapy, due to their high differentiation and self-renewal capacities. Although disruption of host circadian clock machinery has been implicated in tumorigenesis, we found low expression levels of clock gene in CSCs, but not in non-CSCs in tumor tissue. Introduction of oncogenes into fibroblasts, prepared from clock gene defective animals, induced malignant transformation of cells which exhibit stemness properties. These results provide molecular link connecting circadian clock with cancer stemness and aid to develop the strategy for treatment of malignant tumors.

Free Research Field

時間薬剤学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果により、細胞のがん化における時計遺伝子の新たな機能的役割が明らかになった。すなわち、時計遺伝子の発現や機能が低下した細胞が形質転換すると、抗がん剤に対しても高い抵抗性を示す悪性度の高いがん幹様細胞が生じ易くなることが判明した。また、この機序として時計遺伝子によってヒストンのアセチル化状態の変化やmiRNAの発現変容が関与することが示唆された。時計遺伝子の発現回復は、がん細胞の浸潤・転移能を低下させたと伴に、その制御下にある因子の機能を阻害すると抗がん剤耐性能も改善したことから、概日時計機構を標的とすることは悪性度の高いがん細胞に対する治療戦略のひとつになる可能性が示唆された。