DDIT4 Facilitates Lymph Node Metastasis via the Activation of NF-kB Pathway and Epithelial-Mesenchymal Transition

This study was aimed to identify a novel metastasis-promoting molecule and elucidate its functional and prognostic roles in cervical cancer. DDIT4 (DNA-damage-inducible transcript 4), a hypoxia-inducible gene, was identified by analyzing multiple microarray databases. The correlation between DDIT4 expression in immunohistochemistry and clinicopathological characteristics in the public database and our cohort was evaluated by statistical analysis. Transwell (R) assay and wound-healing assay to determine cell migration and invasion were performed. DDIT4 was knocked down using siRNA or lentiviral vectors. The potential downstream pathways of DDIT4 were explored and verified by a gene set enrichment analysis and western blotting. The in vivo metastatic capability was determined with the use of an intraperitoneal injection mouse model. In the analysis of the public database and our cohort, DDIT4 high expression was significantly related to short overall survival and lymph node metastasis in patients with early-stage cervical cancer. The knockdown of DDIT4 attenuated the migration and invasion activity of tumor cells in vitro and reduced the expression of epithelial-mesenchymal transition (EMT)-related proteins and the NF-?B pathway in cervical cancer cells. DDIT4 also promoted tumor progression in the mouse model. Our results indicate that DDIT4 can be a prognostic indicator in cervical cancer and promote lymph node metastasis, augmenting malignancy via the EMT and NF-kB pathways.

Automated summary

This study aimed to identify and elucidate the functional and prognostic roles of a novel metastasis-promoting molecule in cervical cancer called DDIT4 (DNA-damage-inducible transcript 4). The study involved analyzing multiple microarray databases, evaluating the correlation between DDIT4 expression and clinicopathological characteristics, conducting in vitro assays to determine cell migration and invasion, exploring potential downstream pathways of DDIT4, and determining in vivo metastatic capability using a mouse model. The results showed that high expression of DDIT4 was significantly related to short overall survival and lymph node metastasis in early-stage cervical cancer patients. Knockdown of DDIT4 attenuated migration and invasion activity in tumor cells, reduced the expression of EMT-related proteins and the NF-κB pathway, and promoted tumor progression in the mouse model.