Yihua Wu

High serum LDL promotes EMT and stemness through LDLR/FOXQ1/NF-κB1 pathway in epithelial ovarian cancer

Epithelial ovarian cancer (EOC), the deadliest gynecological malignancy, is increasingly linked to dysregulated lipid metabolism. Nevertheless, the involvement of circulating low-density lipoprotein (LDL) in ovarian cancer progression remains controversial. Analyses of single-cell RNA sequencing and clinical data demonstrated a positive correlation between elevated LDL levels and EOC progression. Mechanistically, LDL internalized via LDL receptor (LDLR) enhanced epithelial-mesenchymal transition (EMT) and stemness in ovarian cancer cells, driven by the upregulation of the key transcription factor FOXQ1. Intriguingly, our investigations unveiled a novel transcriptional complex comprising FOXQ1/β-Catenin/ADNP. Both β-Catenin and ADNP interacted with FOXQ1 at the Forkhead domain, where FOXQ1 bound to the NF-κB1 gene promoter to enhance transcriptional activation. Notably, β-Catenin and ADNP were identified for the first time as competitive repressors within this regulatory axis. These findings were further corroborated in vivo using an ovarian cancer xenograft metastasis model, as well as in human pathological specimens, highlighting LDL-driven metastasis via FOXQ1 upregulation. Collectively, LDL promotes ovarian cancer metastasis through LDLR/FOXQ1/NF-κB1 axis. Furthermore, we discover a novel transcriptional complex, where FOXQ1 acts as the central regulator while β-Catenin/ADNP serve as co-repressors. These insights suggest that modulating serum LDL levels or targeting FOXQ1 may offer promising strategies to curb ovarian cancer progression. LDL promotes ovarian cancer metastasis through LDLR/FOXQ1/NF-κB1 axis. High serum LDL uptake mediated by LDLR enhances EMT and stemness of ovarian cancer cells via upregulating FOXQ1 expression. Both β-Catenin and ADNP interact with FOXQ1 in the Forkhead domain (FH), also where FOXQ1 binds to NF-κB1 gene promoter to active its transcription, suggesting that β-Catenin and ADNP may act as competitive repressors in this novel transcriptional regulatory complex. Thus, controlling serum LDL levels and targeting FOXQ1 may be effective interventions for preventing metastasis in women with ovarian cancer.

Bisphenols exposure at environmentally relevant dose promoted ovarian cancer progression and modulated tumor microenvironment through β-catenin/SPP1 axis

Bisphenol A (BPA) and its substitute, Bisphenol S (BPS) are typical endocrine-disrupting chemicals used in plastics, but their cancer-promoting effect has remained controversial. Here, we investigated the effects of environmentally relevant doses of BPA/BPS exposure on the tumor microenvironment (TME) in ovarian cancer. BPA exposure levels was exhibiting a declining trend and BPS showing an ascending trend in the female population by analyzing the NHANES data (2013-2016). Low doses of BPA/BPS both significantly promoted the migration and invasion of ovarian cancer cells in a dose-dependent manner by activating the Wnt/β-catenin signaling pathway, thereby facilitating the SPP1 gene transcription. Notably, low-dose BPA/BPS exposure stimulated ovarian cancer cells to secrete OPN protein (coded by the SPP1 gene), subsequently inducing the transformation of fibroblasts into cancer-associated fibroblasts (CAFs), which could reshape the TME of ovarian cancer. Two in-vivo experiments established with nude mice and SPP1

MAP4K4 promotes ovarian cancer metastasis through diminishing ADAM10-dependent N-cadherin cleavage

AbstractPeritoneal metastasis is a key feature of advanced ovarian cancer, but the critical protein required for ovarian cancer metastasis and progression is yet to be defined. Thus, an unbiased high throughput and in-depth study is warranted to unmask the mechanism. Transcriptomic sequencing of paired primary ovarian tumors and metastases unveiled that MAP4K4, a serine/threonine kinase belongs to the Ste20 family of kinases, was highly expressed in metastatic sites. Increased MAP4K4 expression in metastasis was further validated in other independent patients, with higher MAP4K4 expression associated with poorer survival, higher level of CA125 and more advanced FIGO stage. Down regulation of MAP4K4 inhibited cancer cell adhesion, migration, and invasion. Notably, MAP4K4 was found to stabilize N-cadherin. Further results showed that MAP4K4 mediated phosphorylation of ADAM10 at Ser436 results in suppression of N-cadherin cleavage by ADAM10, leading to N-cadherin stabilization. Pharmacologic inhibition of MAP4K4 abrogated peritoneal metastases. Overall, our data reveal MAP4K4 as a significant promoter in ovarian cancer metastasis. Targeting MAP4K4 may be a potential therapeutic approach for ovarian cancer patients.