Jongmin Kim

Dihydroartemisinin inhibits metastatic potential and cancer stemness by modulating the miR-200b–BMI-1/VEGF-A axis in ovarian cancer

Abstract Despite therapeutic advances, ovarian cancer remains a major clinical challenge owing to its frequent metastasis and chemoresistance, which are often driven by cancer stem cells (CSCs) and proangiogenic signaling. Here we demonstrated that dihydroartemisinin (DHA), a derivative of the antimalarial drug artemisinin, inhibits CSC characteristics, tumor neovascularization and resistance to carboplatin via a microRNA-dependent mechanism in ovarian cancer. DHA substantially inhibited CSC properties, tumorigenicity and vascular endothelial growth factor A (VEGF-A)-mediated tumor neovascularization in ovarian cancer. Moreover, the combined treatment with DHA and carboplatin produced a synergistic effect that reduced tumor burden, chemoresistance and peritoneal dissemination in vivo. Mechanistically, DHA downregulated BMI-1 and VEGF-A/vascular endothelial growth factor receptor 2 (VEGFR2), which are critical factors in CSC maintenance and metastasis, via the upregulation of miR-200b. An analysis of ovarian tumor tissues collected from patients enrolled in our clinical cohort revealed that dual positivity for BMI-1 and VEGF-A was associated with poor progression-free survival. Overall, DHA targets the miR-200b–BMI-1/VEGF-A axis to suppress cancer stemness and metastatic potential, highlighting its therapeutic promise in overcoming the limitations of standard chemotherapy for ovarian cancer. The clinical trial number for this study is not applicable.

Loss of primary cilia promotes EphA2 ‐mediated endothelial‐to‐mesenchymal transition in the ovarian tumor microenvironment

Endothelial‐to‐mesenchymal transition (EndMT) is closely associated with tumor progression. Endothelial cells (ECs) in the tumor microenvironment (TME) use EndMT programs to facilitate tumor progression; however, the underlying mechanisms in ovarian cancer are poorly understood. Here, we describe the involvement of primary cilia in EndMT of the ovarian TME. We showed that ECs from human ovarian tumors displayed robust EndMT and impaired cilia formation, as was also observed in ECs in response to ovarian cancer cell culture‐conditioned media (OV‐CM). Notably, ECs lacking primary cilia exhibited increased OV‐CM‐induced EndMT. Vascular abnormalities, such as enhanced cell migration and vessel permeability, were observed in vitro . Furthermore, in vivo experiments using endothelial‐specific kinesin family member 3A ( Kif3a )‐knockout mice showed enhanced EndMT in the ovarian TME. Mechanistically, we identified ephrin type‐A receptor 2 (EphA2) as a key regulator of EndMT. Upon OV‐CM treatment, EphA2 expression increased, and depletion of EphA2 in ECs decreased OV‐CM‐induced EndMT and vascular abnormalities. These results highlight that the loss of primary cilia and the consequent EphA2 activation are key mechanisms by which EndMT programs induce the acquisition of cancer‐associated fibroblast‐like cells in the ovarian TME, thereby promoting ovarian cancer progression.