Engineered Exosomes Restore miR-508-5p Expression in Uterine Corpus Endometrial Carcinoma and Reduce Tumor Progression and Metastasis by Targeting DLL3

Yue-Ying Li ¹ Hui Liu ² Jia-Lu Feng ³ Wen-Yan Tian ¹ JUAN Du ⁴ Li-Ping Zhang ^4*

• ¹ Tianjin Medical University General Hospital, Tianjin, China
• ² Hubei University of Medicine, Shiyan, Hubei, China
• ³ Wuhan University of Science and Technology, Wuhan, Hubei Province, China
• ⁴ Wuhan Children’s Hospital, Wuhan, China

Endometrial cancer (EC) is an increasing concern among women worldwide, with both genetic and environmental factors contributing to its development. This study investigates the roles of Delta-like ligand 3 (DLL3) and microRNA-508-5p (miR-508-5p) in EC progression. Additionally, a therapeutic approach involving engineered exosomes to interfere with their expression is developed. Utilizing data from The Cancer Genome Atlas (TCGA), elevated DLL3 expression in EC is identified, which correlates with poor patient outcomes. Experimental validation demonstrates that reducing DLL3 expression inhibits EC cell proliferation and metastasis. Furthermore, miR-508-5p downregulation is observed in uterine corpus endometrial (UCEC), with bioinformatics analysis indicating that miR-508-5p targets DLL3. Functional assays confirm the regulatory interaction between miR-508-5p and DLL3, elucidating their roles in EC pathogenesis. Moreover, based on these findings, engineered mesenchymal stem cells were developed to overexpress miR-508-5p, and exosomes were collected using gradient density ultracentrifugation. The engineered exosomes restored miR-508-5p expression in UCEC tumor cells and inhibited DLL3 expression, leading to tumor regression in cell-derived xenograft (CDX) mouse models and a reduction in metastatic foci in a lung metastasis model. These findings suggest potential diagnostic and therapeutic avenues for EC management.