Loss of NAMPT in intestinal epithelium promotes colitis-associated colorectal cancer development
- 주제(키워드) NAMPT , NAD+ , Colitis , Colitis-associated colorectal cancer (CAC) , Azoxymethane (AOM)
- 주제(DDC) 570
- 발행기관 아주대학교 일반대학원
- 지도교수 You-Sun Kim
- 발행년도 2025
- 학위수여년월 2025. 8
- 학위명 석사
- 학과 및 전공 일반대학원 의생명과학과
- 실제URI http://www.dcollection.net/handler/ajou/000000035113
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Nicotinamide phosphoribosyltransferase (NAMPT) is a critical enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD+), a cofactor essential for cellular signaling, energy metabolism, and redox regulation. Previous studies have reported significant NAD+ depletion in the colonic tissues of patients with ulcerative colitis and in mice with experimental colitis. However, the specific role of epithelial NAD+ in supporting intestinal homeostasis remains poorly understood. In this study, I investigated the role of epithelial NAMPT in maintaining intestinal integrity through NAD+ supply, utilizing mice with intestinal epithelial cell (IEC)-specific deletion of Nampt (NAMPTΔIEC). These mice exhibited severe colitis during early life, which progressed to mild chronic inflammation persisting up to 13 months of age. Notably, more than 60% of NAMPTΔIEC mice spontaneously developed colitis-associated colorectal cancer (CAC) after 9 months. Moreover, the injection of Azoxymethane (AOM), a genotoxic carcinogen, accelerated the onset of CAC in NAMPT-deficient mice. Collectively, these findings suggest that epithelial NAD+ depletion caused by NAMPT deficiency predisposes to colon cancer by driving an inflamed microenvironment. This study highlights epithelial NAMPT as a potential therapeutic target for the treatment of inflammatory bowel disease and CAC.
more목차
I. INTRODUCTION 1
II. MATERIALS AND METHODS 3
A. Mice 3
B. Histology and Immunofluorescence 3
C. Isolation of colon lamina propria cells 4
D. Flow cytometric analysis 4
E. Measurement of NAD 5
F. Western blotting 5
G. Quantitative RT-PCR 5
H. AOM-induced murine colon cancer 6
I. Exome sequencing 6
III.RESULTS 8
A.Establishment of gut epithelium-specific NAMPT knockout mouse. 8
B. Deletion of NAMPT in the intestinal epithelium leads to severe colitis. 11
C. NMN administration rescues NAMPT deficiency-induced colitis. 14
D.NAMPT deficiency in intestinal epithelium leads to colon cancer. 19
E.NAMPT∆IEC mice are more susceptible to AOM 30
F.Early-life colitis plays a critical role in the development of colitis-associated colorectal cancer. 36
IV. DISCUSSION 39
V. REFERENCES 42
국문요약 45
