DDIT4 overexpression promotes cervical cancer metastasis via the activation of an epithelial–mesenchymal transition

Metastasis is a major challenge in the treatment of cervical cancer patients. This study was aimed to identify a novel metastasis-promoting molecule and elucidate its functional role in cervical cancer. Multiple databases was used to identify molecules associated with metastasis of cervical cancer. DDIT4 (DNA-damage-inducible transcript 4), a hypoxia-inducible gene, was identified in this analysis. Correlation between DDIT4 expression and lymph node metastasis was evaluated by immunohistochemistry. Transwell® assay and wound-healing assay to determine cell migration and invasion was performed. DDIT4 was knocked down using siRNA and lentiviral vectors. The potential downstream effects of DDIT4 were explored and verified by a gene set enrichment analysis and western blotting. The in vivo metastatic capability of cervical cancer regulated by DDIT4 was determined with the use of an intraperitoneal-injection mouse model. DDIT4 was an independent prognostic factor for patients with early-stage cervical cancer, according to both public database and our cohort. In our clinical samples, the expression of DDIT4 in immunohistochemistry was strongly associated with metastasis and hypoxia. 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-κB pathway in cervical cancer cells. DDIT4 also promoted metastasis in the mouse model. Our results define the DDIT4 as a novel metastasis-promoting pathway of EMT and NF-κB pathway that mediates cancer migration and invasion. DDIT4 may thus become a prognostic marker and a potential target for cervical cancer metastasis.