期刊
EMBO REPORTS
卷 20, 期 4, 页码 -出版社
WILEY
DOI: 10.15252/embr.201847638
关键词
Annexin A1; colorectal cancer; FadA; Fusobacterium nucleatum; two-hit model
资金
- NIH [RO1CA192111, RO1DE014924, RO1DE023332, P30 CA013696]
- Damon Runyon-Rachleff Innovation Award from the Damon Runyon Cancer Research Foundation [DRR-44-16]
Fusobacterium nucleatum, a Gram-negative oral anaerobe, is a significant contributor to colorectal cancer. Using an in vitro cancer progression model, we discover that F. nucleatum stimulates the growth of colorectal cancer cells without affecting the pre-cancerous adenoma cells. Annexin A1, a previously unrecognized modulator of Wnt/beta-catenin signaling, is a key component through which F. nucleatum exerts its stimulatory effect. Annexin A1 is specifically expressed in proliferating colorectal cancer cells and involved in activation of Cyclin D1. Its expression level in colon cancer is a predictor of poor prognosis independent of cancer stage, grade, age, and sex. The FadA adhesin from F. nucleatum up-regulates Annexin A1 expression through E-cadherin. A positive feedback loop between FadA and Annexin A1 is identified in the cancerous cells, absent in the non-cancerous cells. We therefore propose a two-hit model in colorectal carcinogenesis, with somatic mutation(s) serving as the first hit, and F. nucleatum as the second hit exacerbating cancer progression after benign cells become cancerous. This model extends the adenoma-carcinoma model and identifies microbes such as F. nucleatum as cancer facilitators.
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