ZEB2 facilitates peritoneal metastasis by regulating the invasiveness and tumorigenesis of cancer stem-like cells in high-grade serous ovarian cancers

Abstract

Peritoneal metastasis is a common issue in the progression of high-grade serous ovarian cancers (HGSOCs), yet the underlying mechanism remains unconfirmed. We demonstrated that ZEB2, the transcription factor of epithelial–mesenchymal transition (EMT), was upregulated in ascites cells from HGSOC patients and in CD133+ cancer stem-like cells (CSLCs) from epithelial ovarian cancer (EOC) cell lines. SiRNA-mediated knockdown of ZEB2 in EOC cells decreased the percentage of CSLCs and reduced the colony forming potential, cell invasion capacity and expression of pluripotent genes Oct4 and Nanog. Inhibition of ZEB2 also induced cellular apoptosis and impacted the tumorigenicity of ovarian CSLCs. The mesenchymal markers N-cadherin and vimentin were downregulated, while the epithelial marker E-cadherin was upregulated after ZEB2 knockdown. MiR-200a, a molecule that downregulates ZEB2, had the opposite effect of ZEB2 expression in EOC-CSLCs. A retrospective study of 98 HGSOC patients on the relationship of ascites volume, pelvic and abdominal metastasis, International Federation of Gynecology and Obstetrics (FIGO) stage and the malignant involvement of abdominal organs and lymph nodes was performed. Patients with high expression of ZEB2 in tumour tissues had a higher metastasis rate and a poorer prognosis than those with low expression. The parameters of ZEB2 expression and ascites volume were strongly linked with the prognostic outcome of HGSOC patients and had higher hazard ratios. These findings illustrated that ZEB2 facilitates the invasive metastasis of EOC-CSLCs and can predict peritoneal metastasis and a poor prognosis in HGSOC patients.

Zinc Finger E-Box Binding Homeobox 2 as a Prognostic Biomarker in Various Cancers and Its Correlation with Infiltrating Immune Cells in Ovarian Cancer

“…Moreover, it correlates with worse PFS, OS, and PPS in grades II + III and III. This result is in agreement with previous studies in OV patients, suggesting its metastatic potential [18,19]. Although its expression was decreased in OV compared to normal tissue, higher EZH2 expression induced peritoneal metastasis, such as cancer stem cells.…”

“…However, ZEB2 is relatively highly expressed in tumors such as leukemia, brain glioma, pancreatic adenocarcinoma, and melanoma. Previous studies suggest that ZEB2 is associated with a bad prognosis in numerous kinds of cancer [18,19,31]. Nevertheless, the prognostic significance of ZEB2 in OV remains unclear.…”

“…ZEB2 is associated with the progression and development of malignancies such as liver cancer, cervical cancer, gastric cancer, and breast cancer [13][14][15][16][17]. Recent studies have shown that ZEB2 promotes peritoneal metastasis, through the process of regulating invasive cells and tumorigenesis of cancer cells in high-grade serous ovarian cancers (HGSOCs) [18]. In addition, ZEB2 had a significant correlation with poor prognosis and could improve EMT conversion in OV [19].…”

Single-cell transcriptome reveals cellular hierarchies and guides p-EMT-targeted trial in skull base chordoma

“…In recent years, several EMT markers have been found to be responsible for chordoma invasion and proliferation 57 . In addition, accumulating evidence shows that ZEB2 plays a pivotal role in EMT-induced malignant mechanisms, including tumor invasion, tumor recurrence 58 , drug resistance 59 , cancer stem-cell-like traits 60 , and metastasis 61 , raising the possibility that ZEB2 -associated p-EMT is involved in SBC invasiveness. According to our scRNA-seq data, the ZEB2 expression did not significantly correlate with the p-EMT program in the level of individual tumor cell.…”

CircCRIM1 promotes ovarian cancer progression by working as ceRNAs of CRIM1 and targeting miR-383-5p/ZEB2 axis

“…Previous study found that miR-383-5p worked as tumor suppressor gene to suppress proliferation of ovarian cancer cells and inhibit progression of gastric cancer [ 39 – 41 ]. While ZEB2 worked as oncogenic genes in ovarian cancer to drive EMT transition, tumorigenesis and peritoneal metastasis [ 42 , 43 ]. The study found that ZEB2 expression in ascites of patients with high-grade serous ovarian cancer was higher than that of primary ovarian cancers.…”