Vitamin D receptor upregulates lncRNA TOPORS-AS1 which inhibits the Wnt/β-catenin pathway and associates with favorable prognosis of ovarian cancer

Sci Rep. 2021 Apr 5;11(1):7484. doi: 10.1038/s41598-021-86923-7.

Abstract

Long non-coding RNAs (lncRNAs) have important biological functions, but their involvement in ovarian cancer remains elusive. We analyzed high-throughput data to identify lncRNAs associated with ovarian cancer outcomes. Our search led to the discovery of lncRNA TOPORS Antisense RNA 1 (TOPORS-AS1). Patients with high TOPORS-AS1 expression had favorable overall survival compared to low expression. This association was replicated in our study and confirmed by meta-analysis. In vitro experiments demonstrated that overexpressing TOPORS-AS1 in ovarian cancer cells suppressed cell proliferation and inhibited aggressive cell behaviors, including migration, invasion, and colony formation. Analysis of tumor cell transcriptomes indicated TOPORS-AS1's influence on the Wnt/β-catenin signaling. Additional experiments revealed that TOPORS-AS1 increased the phosphorylation of β-catenin and suppressed the expression of CTNNB1, disrupting the Wnt/β-catenin pathway. Our experiments further discovered that vitamin D receptor (VDR) upregulated TOPORS-AS1 expression and that inhibition of β-catenin by TOPORS-AS1 required a RNA binding protein, hnRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2B1). Taken together, these findings suggest that TOPORS-AS1 may behave like a tumor suppressor in ovarian cancer through interrupting the Wnt/β-catenin signaling and that VDR upregulates the expression of TOPORS-AS1. Assessing TOPORS-AS1 expression in ovarian cancer may help predict disease prognosis and develop treatment strategy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Humans
  • Kaplan-Meier Estimate
  • Middle Aged
  • Models, Biological
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Prognosis
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • Receptors, Calcitriol / metabolism*
  • Survival Analysis
  • Transcriptome / genetics
  • Tumor Stem Cell Assay
  • Up-Regulation / genetics*
  • Wnt Signaling Pathway* / genetics
  • beta Catenin / metabolism

Substances

  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • RNA, Long Noncoding
  • Receptors, Calcitriol
  • VDR protein, human
  • beta Catenin
  • hnRNP A2