Abstract
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 II colon cancer. DDA1, an evolutionarily conserved gene located at 19p13.11, may be involved in the activation of nuclear factor kappaB (NFκB). This study aimed to investigate whether DDA1 contributes to tumorigenesis and progression of stage II colon cancer via activation of the NFκB 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 IIB–IIC 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 NFκB/COP9 signalosome 2(CSN2)/glycogen synthase kinase3β (GSK3β) pathway. These results indicate that DDA1 promotes colon cancer progression through activation of NFκB/CSN2/GSK3β signaling. DDA1, together with NFκB activation status, may serve as a sensitive biomarker for tumor recurrence risk and prognosis in patients with stage IIB–IIC colon cancers.
Highlights
Risk of tumor recurrence is clinically determined based on the pathological characteristics of the tumor
We report that (1) DDA1 and nuclear p65 levels were increased in stage II colon cancers, (2) both DDA1 and nuclear p65 levels were significantly higher in tumors of patients with relapsed stage II cancer as compared to nonrelapsed stage II, (3) positive expression of DDA1 either alone or in combination with p65 nuclear translocation was associated with poor prognosis in stage II colon cancer, especially in stage IIB–IIC patients, and (4) DDA1 promoted proliferation, increased cell cycle S-phase arrest, inhibited 5-FU-induced apoptosis, and promoted invasion and the epithelial–mesenchyme transition (EMT) through the NFκB/CSN2/glycogen synthase kinase3β (GSK3β) pathway
We observed that DDA1 predicts tumor recurrence and poor prognosis in patients with stage II colon cancer, especially for patients with stage IIB–IIC disease undergoing post-operative chemotherapy with 5-FU/lentiviral expressing (LV) or FOLFOX4
Summary
Risk of tumor recurrence is clinically determined based on the pathological characteristics of the tumor. It is widely accepted that mutations in various genes, such as in APC, KRAS, p53, and BRAF, are involved in colon cancer tumorigenesis and progression [10,11,12] These genes have been extensively explored in stage II colon cancer for identifying the risk of tumor recurrence and for predicting chemosensitivity [13]. Their roles in evaluating the benefits of chemotherapy following tumor relapse have not been widely explored in the clinical setting. To better design a strategy for individualized chemotherapy, it is pivotal that researchers identify biomarkers that participate in colon cancer tumorigenesis and progression, and predict chemosensitivity and the risk of tumor recurrence in patients with stage II cancer
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