DDA1 Promotes Stage ?B–?C Colon Cancer Progression By Activating NF?B/CSN2/GSK-3? Signaling

Conventional high-recurrence risk factors are not sufficient to predict post-operative risk of tumor recurrence or sensitivity to 5-fluorouracil(5-FU)-based chemotherapy for stage ? colon cancer.DDA1,an evolutionarily conserved gene located at 19p13.11,may be involved in the activation of nuclear factor kappa B(NF?B).This study aimed to investigate whether DDA1 contributes to tumorigenesis and progression of stage ? colon cancer via activation of the NF?B pathway.We found that positive expression of DDA1 alone or in combination with p65 nuclear translocation correlated with increased risk of tumor recurrence in patients with stage ?B–?C colon cancer.DDA1 overexpression in colon cancer lines promoted cell proliferation,facilitated cell cycle progression,inhibited 5-FU-induced apoptosis,enhanced invasion,and induced the epithelial-mesenchymal transition.Suppression of DDA1 inhibited tumor progression,and reduced tumor growth in vivo.We also demonstrated that DDA1-mediated tumor progression is associated with the activation of the NF?B/COP9 signalosome 2(CSN2)/glycogen synthase kinase3?(GSK3?)pathway.These results indicate that DDA1 promotes colon cancer progression through activation of NF?B/CSN2/GSK3? signaling.DDA1,together with NF?B activation status,may serve as a sensitive biomarker for tumor recurrence risk and prognosis in patients with stage ?B–?C colon cancers.