Ovo Like Zinc Finger 2 (OVOL2) Suppresses Breast Cancer Stem Cell Traits and Correlates with Immune Cells Infiltration

Abstract

Background Breast cancer stem cells (BCSCs) are associated with tumor initiation, invasion, metastasis and drug resistance. It is known that many proteins and signaling pathways are involved in the regulation of BCSCs, however, much more efforts are needed to understand BCSCs comprehensively. Tumor-infiltrating immune cells are important in cancer treatment efficacy and patient prognosis. We tried to identify potential suppressor of BCSCs and analyze its correlation with various immune cells infiltration by bioinformatic and experimental methods. Methods Expression level and methylation state of OVOL2 were analyzed by tools from bc-GenExMiner v4.8 and UALCAN databases. The Kaplan–Meier plotter was applied to evaluate the prognostic values of OVOL2. Gene expression datasets (GSE7515, GSE15192) were selected to analyze differentially expressed genes (DEGs) related to BCSCs. GO and KEGG pathway analyses of DEGs were conducted. MCODE app plugin of Cytoscape was used to screen modules in PPI network of downregulated DEGs. Correlation of OVOL2 expression with infiltrating immune cells was evaluated by TIMER 2.0. Experiments were conducted to verify whether OVOL2 could inhibit stemness traits of breast cancer cell MDA-MB-231. Results The expression level of OVOL2 in basal/TNBC was significantly lower than that of other subtypes. Survival analyses indicated that high expression of OVOL2 was associated with favorable prognosis. GO and KEGG pathway analyses for upregulated and downregulated DEGs were conducted. The top three clusters of downregulated DEGs showed that tight junction and chemokines may play important roles in BCSCs. OVOL2 is one module of clusters. OVOL2 expression is correlated with various immune cells infiltration. Experiments showed that OVOL2 suppresses CD44 + /CD24 − ratio and mammospheres formation of MDA-MB-231. Conclusion OVOL2 may play an important role in the regulation of breast cancer stemness and immune cell infiltration, and is likely to be a target for the treatment of breast cancer.

“Pulsed Hypoxia” Gradually Reprograms Breast Cancer Fibroblasts into Pro-Tumorigenic Cells via Mesenchymal–Epithelial Transition

“…Garcia et al have also shown that Ovol1 and Ovol2 modify the transcriptome of mesenchymal breast cancers cells by downregulation of the mesenchymal markers [72]. Moreover, Wu et al have shown that OVOL2 suppressed stem cells population (CD44+/CD24−) in mesenchymal MDA-MB-231 cells [73]. We have also found a high number of CD44+/CD24− cells in BrC4f CAFs and in cells with transitional phenotypes (Figure S4) that may correlate with their potential to migrate to distant metastatic locuses.…”