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Hypoxia-repressed lncRNA ZNF213-AS1 restrains p65-driven epithelial-mesenchymal transition in ovarian cancer
Caixia Li1, Rong Chen1, Yujie Zhao2
1Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
Abstract:
Hypoxia promotes ovarian cancer progression, EMT and platinum resistance, but the lncRNA mediators involved remain unclear. Here, we identified ZNF213-AS1 as a downregulated lncRNA in ovarian cancer by analyzing TCGA-OV and GTEx datasets. Low ZNF213-AS1 expression predicted poor overall survival and was associated with hypoxia, EMT, NF-κB and IL6/JAK/STAT3 signatures. ZNF213-AS1 was relatively abundant and enriched in the chromatin-associated fraction. Hypoxia reduced ZNF213-AS1 expression in ovarian cancer cells, but this repression was not rescued by HIF1α knockout or mutation of the predicted HRE motif, suggesting a noncanonical hypoxic regulatory mechanism. Functionally, ZNF213-AS1 overexpression suppressed hypoxia-induced colony formation, invasion and cisplatin resistance, whereas ZNF213-AS1 knockdown enhanced these phenotypes. Mechanistically, ZNF213-AS1 inhibited NF-κB reporter activity and reduced NF-κB/STAT3/EMT-related gene expression. RNA pull-down and RIP assays showed that ZNF213-AS1 associates with RELA/p65-containing NF-κB complexes. Moreover, p65 re-expression partially reversed the inhibitory effects of ZNF213-AS1 on STAT3 activation, EMT markers and xenograft growth. These findings define a hypoxia-repressed ZNF213-AS1-p65 axis that limits NF-κB/STAT3-driven EMT and platinum-resistant ovarian cancer progression.
Insights
Hypoxia decreases ZNF213-AS1, a long noncoding RNA, in ovarian cancer. This promotes tumor growth, invasion, and platinum resistance by activating NF-κB and STAT3 signaling pathways.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Hypoxia is a key driver of ovarian cancer progression, epithelial-mesenchymal transition (EMT), and platinum resistance.
- The specific long noncoding RNAs (lncRNAs) mediating these hypoxia-induced effects in ovarian cancer are not fully understood.
Purpose of the Study:
- To identify and characterize the role of lncRNAs involved in hypoxia-driven ovarian cancer progression.
- To elucidate the molecular mechanisms by which ZNF213-AS1 regulates ovarian cancer aggressiveness and platinum resistance under hypoxic conditions.
Main Methods:
- Analysis of TCGA-OV and GTEx datasets to identify differentially expressed lncRNAs.
- In vitro studies involving ovarian cancer cell lines to assess the functional impact of ZNF213-AS1.
- RNA pull-down and RIP assays to determine molecular interactions.
- Xenograft models to evaluate therapeutic potential.
Main Results:
- ZNF213-AS1 was identified as a downregulated lncRNA in ovarian cancer, with low expression correlating with poor survival and aggressive phenotypes.
- Hypoxia repressed ZNF213-AS1 expression via a noncanonical mechanism, independent of HIF1α.
- ZNF213-AS1 overexpression suppressed hypoxia-induced proliferation, invasion, and cisplatin resistance, while knockdown enhanced these effects.
- ZNF213-AS1 directly interacted with NF-κB (RELA/p65) complexes, inhibiting NF-κB/STAT3 signaling and downstream EMT-related gene expression.
Conclusions:
- A hypoxia-repressed ZNF213-AS1-p65 axis was defined, which suppresses NF-κB/STAT3-driven EMT and platinum-resistant ovarian cancer progression.
- ZNF213-AS1 acts as a tumor suppressor by inhibiting key oncogenic signaling pathways activated by hypoxia.
- Targeting the ZNF213-AS1 pathway may offer a novel therapeutic strategy for overcoming platinum resistance in ovarian cancer.
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