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
Highlights
Abbreviations long non-coding RNAs (lncRNAs) Long non-coding RNAs TOPORS-AS1 TOPORS Antisense RNA vitamin D receptor (VDR) Vitamin D receptor MEG3 Maternally expressed gene 3 Hazard ratios (HR) Hazard ratio confidence interval (CI) Confidence interval OS Overall survival PFS Progression free survival differentially expressed genes (DEGs) Differentially expressed genes LEF1 Lymphoid enhancer-binding factor 1 TCF1/TCF7 Transcription Factor 7 GSK3β Glycogen synthase kinase 3 beta hnRNPA2B1 Heterogeneous nuclear ribonucleoproteins A2/B1
High expression of TOPORS-AS1 was found to be associated with favorable overall survival, and the association remained significant after adjusting for patient age, disease stage, tumor grade and histology (Table 2)
Our experiments showed that VDR expression did not change over time in IGROV1 and SKOV3 after TOPORS-AS1 transfection (Fig. 5J,L), but cell proliferation was suppressed in the transfected cells (Fig. 5I,K), indicating that TOPORS-AS1 does not affect the expression of VDR and the lncRNA suppresses cell proliferation, not VDR
Summary
Abbreviations lncRNAs Long non-coding RNAs TOPORS-AS1 TOPORS Antisense RNA VDR Vitamin D receptor MEG3 Maternally expressed gene 3 HR Hazard ratio CI Confidence interval OS Overall survival PFS Progression free survival DEGs Differentially expressed genes LEF1 Lymphoid enhancer-binding factor 1 TCF1/TCF7 Transcription Factor 7 GSK3β Glycogen synthase kinase 3 beta hnRNPA2B1 Heterogeneous nuclear ribonucleoproteins A2/B1. Since protein-coding genes account for only 2% of the human genome[2], our understanding of ovarian cancer development and progression from the genome perspective remains inadequate. Emerging evidence suggests that lncRNAs play a role in cancer, including ovarian cancer[3,4,5,6,7,8,9]. Our search led us to find the expression of TOPORS Antisense RNA 1 (TOPORS-AS1) significantly associated with overall and progression-free survival of ovarian cancer. Increasing VDR expression in ovarian cancer cells inhibits cell proliferation and tumor g rowth[15]. We discussed our discovery of lncRNA TOPORS-AS1 whose expression was regulated by VDR, associated with ovarian cancer survival, and able to inhibit the Wnt/β-catenin signaling
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