TY - JOUR
T1 - DDIT4 Facilitates Lymph Node Metastasis via the Activation of NF-κB Pathway and Epithelial-Mesenchymal Transition
AU - Lin, Xinxin
AU - Yoshikawa, Nobuhisa
AU - Liu, Wenting
AU - Matsukawa, Tetsuya
AU - Nakamura, Kae
AU - Yoshihara, Masato
AU - Koya, Yoshihiro
AU - Sugiyama, Mai
AU - Tamauchi, Satoshi
AU - Ikeda, Yoshiki
AU - Yokoi, Akira
AU - Shimizu, Yusuke
AU - Kajiyama, Hiroaki
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Society for Reproductive Investigation.
PY - 2023/9
Y1 - 2023/9
N2 - 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® 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-κB 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.
AB - 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® 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-κB 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.
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U2 - 10.1007/s43032-023-01230-y
DO - 10.1007/s43032-023-01230-y
M3 - Article
C2 - 37016173
AN - SCOPUS:85151549302
SN - 1933-7191
VL - 30
SP - 2829
EP - 2841
JO - Reproductive Sciences
JF - Reproductive Sciences
IS - 9
ER -
