Identification of the mechanism by which E-NTPD8 regulates development of colorectal cancer by hydrolysis of commensal bacteria-dependent ATP

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08881
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Osaka University
• Principal Investigator: Kayama Hisako 大阪大学, 高等共創研究院, 准教授 (40548814)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: ATP / E-NTPD8 / 腸炎 / 大腸癌 / P2RX4

Outline of Final Research Achievements

E-NTPD8 was highly expressed in the apical aspect of epithelia cells of the colon. Entpd8-deficent mice showed higher levels of ATP in feces than that in wild-type mice. Entpd8-eifceint mice developed severe colitis during administration of dextran sodium sulfate (DSS). In this context, Entpd8-deficeint mice exhibited increased number of neutrophils in the colonic lamina propria. In addition, Entpd8-deifceint mice suffered from severe colitis-associated colorectal cancer following treatment with azoxymethane plus DSS. Introduction of the P2rx4 deficiency into Entpd8-deficeint mice drastically reduced large intestinal pathology with decreased number of neutrophils during DSS administration. Treatment with ATPgS induced prolonged life span of neutrophils isolated from the colon of wild-type mice, but not P2rx4-deficent mice. These findings demonstrate that E-NTPD8 in intestinal epithelial cells prevents neutrophil-mediated exacerbation of colitis via P2RX4 by hydrolysis of luminal ATP.

Free Research Field

粘膜免疫

Academic Significance and Societal Importance of the Research Achievements

潰瘍性大腸炎とクローン病に大別される炎症性腸疾患(IBD)は、大腸や小腸の粘膜に慢性の炎症や潰瘍が生じる難治性疾患である。IBDは、「遺伝的素因」「環境」「腸内細菌」「上皮バリア」「免疫応答」が複雑に関わり合う多因子疾患のため未だ根治的治療法が確立していない。上皮細胞に発現する膜型ATP分解酵素E-NTPD8による腸内細菌由来の腸管腔内ATP分解がP2RX4シグナルを介した好中球による腸管炎症増悪を抑制することを明らかにした本研究の成果は、ATP/E-NTPD8/P2RX4といったIBD治療法の新規標的分子を同定した点で非常に意義深いものといえる。