OncoTargets and Therapy (Jan 2021)
GADD45B Facilitates Metastasis of Ovarian Cancer Through Epithelial–Mesenchymal Transition
Abstract
Lanqing Gong,1,* Liqiong Cai,1,* Guodong Li,2 Jing Cai,1 Xiaoqing Yi1 1Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People’s Republic of China; 2Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoqing YiDepartment of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People’s Republic of ChinaTel/Fax: +86 27 85351649Email [email protected]: Growth arrest and DNA-damage-inducible 45 beta (GADD45B) is overexpressed and is associated with poor clinical outcomes in many human cancers, but the clinical implication of GADD45B in epithelial ovarian cancer (EOC) remains unclear.Methods: Bioinformatics analysis of The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) cohorts was used to illustrate the relationship between GADD45B expression and metastasis, as well as the survival time of EOC. GADD45B was downregulated by siRNAs in EOC cells, and migration ability was determined by a transwell assay and wound-healing assay. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene set enrichment analysis (GSEA) were conducted to discover the downstream pathway of GADD45B. The regulation of epithelial–mesenchymal transition (EMT) by GADD45B was verified by Western blotting and qRT-PCR. Finally, the correlation of GADD45B expression with EOC metastasis was investigated in EOC tissues by immunohistochemistry.Results: Overexpression of GADD45B indicates shorter overall survival time and progression-free survival time, and it is an independent risk factor for poor survival in EOC patients. Elevated GADD45B is related to venous invasion, lymphatic invasion and peritoneal carcinomatosis. Downregulation of GADD45B decreases the migration of ES2 and SKOV3 cells. Further KEGG enrichment analysis and GSEA revealed that EMT may be the downstream pathway of GADD45B. In addition, reduced GADD45B increases the expression of E-cadherin and decreases that of N-cadherin and vimentin. Finally, immunohistochemical analysis of GADD45B expression revealed that the expression of GADD45B in omental metastatic tissues was higher than that in matched primary ovarian cancer tissues. These results suggest that elevated GADD45B promotes the motility of ovarian cancer cells through EMT and is associated with EOC metastasis.Conclusion: GADD45B can promote the motility of ovarian cancer cells through EMT, is associated with EOC metastasis, and may be a new biomarker of metastasis and prognosis.Keywords: epithelial ovarian cancer, GADD45B, metastasis, epithelial–mesenchymal transition
