Jun Liang

Inhibition of PI3K and Hedgehog Signaling Pathway Inhibits Hypoxia-Induced Vasculogenic Mimicry Formation in Ovarian Cancer Stem Cells

Inhibition of the Hedgehog and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathways has been shown to suppress tumor proliferation and stem cell activity. However, the precise role of these pathways in vasculogenic mimicry (VM) of ovarian cancer stem cells (OCSCs) remains unclear. To investigate the roles of the PI3K/AKT and Hedgehog signaling pathways in VM formation and the underlying mechanisms in OCSCs. OCSCs were induced through serum-free culture of SK-OV-3. Hypoxia-inducible factor-1α (HIF-1α) knockdown was achieved by transfection with sh-HIF-1α. Cells were treated with the PI3K agonist 740 Y-P, the PI3K inhibitor LY294002, the Hedgehog agonist purmorphamine, and the Hedgehog inhibitor cyclopamine under hypoxic conditions. Expression of HIF-1α, epithelial-to-endothelial transition (EET) markers, and components of the PI3K and Hedgehog pathways was analyzed using immunofluorescence and Western blotting. VM capacity was assessed using a Matrigel three-dimensional (3D) culture assay. Cell proliferation and invasion were evaluated by MTS, EdU, and Transwell assays. VM formation was further examined in an OCSC xenograft model. OCSCs accounted for more than 85% of seventh-generation SK-OV-3 cells cultured under serum-free conditions. Hypoxia markedly increased HIF-1α expression, which activated the PI3K and Hedgehog signaling pathways. HIF-1α knockdown suppressed activation of these pathways. Treatment with LY294002 and cyclopamine, as well as HIF-1α knockdown, inhibited hypoxia-induced upregulation of N-cadherin and VE-cadherin, as well as the formation of branching points and 3D channels. Moreover, both LY294002 and cyclopamine significantly reduced cell proliferation, invasion, and VM formation in vitro and in xenografted OCSCs. HIF-1α knockdown inhibits activation of the PI3K and Hedgehog signaling pathways, thereby reducing EET and VM formation in hypoxia-induced OCSCs.

Research Progress of RAD51AP1 in Malignant Tumors of the Female Reproductive System

ABSTRACT Genomic instability may contribute to the occurrence and progression of malignant tumors of the female reproductive system. Homologous recombination repair (HRR) is vital in maintaining cellular genomic stability. RAD51‐associated protein 1 (RAD51AP1) plays a vital role in HRR, mainly participating in the formation of displacement loop (D‐loop), and is an important molecule for maintaining cellular genomic stability. Recent studies showed that RAD51AP1 was significantly overexpressed in a variety of cancer types and correlated with prognosis, suggesting that it may have a significant pro‐carcinogenic effect. However, the mechanism underlying its pro‐carcinogenic effect remains unclear, which may be closely associated with cancer stemness. Meanwhile, RAD51AP1 also plays an important role in resistance to radiotherapy and chemotherapy. Exploring RAD51AP1 and its regulatory molecules may provide new targets for overcoming cancer progression and treatment resistance. Here, we reviewed the latest research on RAD51AP1 in female reproductive system tumors and summarized its differential expression and prognostic implications. In this review, we also outlined the potential mechanisms of its procancer and drug resistance‐promoting effects to provide several potential directions for further research.