Analysis of the effect of hypoxia-induced downregulation of soluble IL-33 receptor on malignant progression of colorectal cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K07673
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Teikyo University
• Principal Investigator: Akimoto Miho 帝京大学, 医学部, 講師 (60437556)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: 大腸がん / 低酸素 / インターロイキンー３３ / GATA3 / 転移抑制

Outline of Final Research Achievements

In the tumor microenvironment of colorectal cancer (CRC), sST2 acts in a tumor-suppressive manner by inhibiting the proinflammatory function of interleukin (IL)-33. This study demonstrates that hypoxia, which is closely associated with tumor malignancy, decreases sST2 expression in CRC cells. Hypoxia-induced sST2 depletion results from hypoxia-inducible factor-dependent nuclear accumulation of IL-33, which binds to GATA3 and blocks its access to the sST2 promoter. Most importantly, restoration of sST2 expression limited to hypoxic regions in mouse CRC tumors improves the inflammatory tumor environment, effectively suppressing tumor growth and metastasis. sST2 depletion is also observed in hypoxic regions of human CRC lesions. Our findings suggest that sST2 enhancement specifically targeting hypoxic tumor regions may be useful in the treatment of malignant CRC.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

大腸がんは本邦において罹患者数の多いがん種の一つであり、今後更なる増加が見込まれる。大腸がんの治療法は進歩を遂げているものの、転移の制御は未だ困難である。そのため、大腸がんの発生・悪性化の機序に関する新たな知見を得ることは大きな意義を持つ。本研究で得られた知見は、腫瘍組織中の低酸素腫瘍領域を標的としたsST2増強が、転移を伴う悪性大腸がんの抑制に有効であることを示すものであり、新たな大腸がん治療戦略への応用の可能性が期待される。