Delta‐like 1 homolog ( DLK1 ) regulates cancer stemness and chemoresistance of ovarian cancer by CD44 / CD133 upregulation

Abstract

Ovarian cancer is a heterogeneous gynecologic malignancy, with most cases diagnosed at an advanced stage. Despite the availability of effective treatments such as surgery and platinum/taxane‐based chemotherapy, advanced ovarian cancer frequently recurs, highlighting the need to investigate mechanisms of chemotherapy resistance. Delta‐like non‐canonical Notch ligand 1 (DLK1), a transmembrane protein of the EGF‐like family, is aberrantly expressed in several cancers. Our previous study demonstrated that DLK1 promotes oncogenic behaviors and epithelial–mesenchymal transition in ovarian high‐grade serous carcinoma. In this study, we observed a positive correlation between DLK1 and stemness markers CD44 and CD133 in human epithelial ovarian cancer using tissue microarray analysis. Overexpression of DLK1 by an adenovirus vector accelerated sphere‐forming capability and upregulated CD44, CD133, and ABCG2 expression in human ovarian cancer cell lines. Conversely, DLK1 silencing by siRNA abolished the stimulatory effects on the stem cell‐like properties and reduced CD44 and CD133 expression in ovarian cancer cells. Furthermore, DLK overexpression by an adenovirus vector enhanced colony formation and suppressed the cisplatin‐ and taxol‐induced death in human ovarian cancer cells. Conversely, DLK1 siRNA reversed cell death and colony formation induced by these chemotherapeutic agents. Finally, we demonstrated that DLK1 regulates CD44, CD133, and ABCG2 expression through the Notch1/AKT/STAT3 signaling pathway, involving the phosphorylation and translocation of STAT3. Collectively, these results suggest that targeting DLK1 may represent a potential therapeutic strategy to improve outcomes in recurrent ovarian cancer following chemotherapy. © 2026 The Pathological Society of Great Britain and Ireland.