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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.

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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