Fusobacterium nucleatum stimulates colorectal carcinogenesis through a key host growth regulator Annexin

ROXANA RUBINSTEIN; JUNGEUN BAIK; STEPHEN M LAGANA; REBECCA H GELLMAN; TIMOTHY C WANG; YIPING HAN

Cold Spring Harbor, NY

Conferencia; 9th International Conference on the Annexins; 2017

Colorectal cancer (CRC) isthe second leading cause of cancer death in men and women combined in the U.S.,affecting one in every 20 individuals. Recent studies have consistentlyimplicated Fusobacterium nucleatum (Fn),a Gram-negative opportunistic oral commensal, in CRC.We have previously reported that Fn stimulates colorectal tumorigenesis via itsunique adhesin, FadA, which binds to E-cadherin and modulates beta-cateninsignaling. We now show that FadA specifically stimulates the growth ofcolorectal carcinoma cells, but not the adenoma cells or breast cancer cells.This cell-type-specific growth stimulation is mediated by Annexin A1, a keyhost component required for CRC cell growth and is expressed at a higher levelin CRC cells than in adenoma cells. Fn preferentially binds to Annexin A1-expressingcells via FadA, which in turn stimulates Annexin A1 expression in CRC cells.FadA, E-cadherin and Annexin A1 co-localize on CRC cells, and interactionbetween all three is required for induction of Annexin A1 expression. IncreasedAnnexin A1 expression leads to accumulation of beta-catenin in the cytoplasmand nuclear translocation. Suppression of E-cadherin expression results inreduced expression of Annexin A1 and suppression of CRC cell growth. In APCmin/+ mice, we observed an increased expression of Annexin A1 in thetumors induced by Fn,compared to the controls. Annexin A1 and FadA also co-localize in human CRCtissues, further supporting their role in CRC pathogenesis. Our study therefore describes a novel mechanismby which Annexin A1 and FadA promote colorectal carcinogenesis.