Abstract
Accumulating evidences have revealed the dysregulated expressions and critical roles of non-coding RNAs in various malignancies, including cervical cancer. Nevertheless, our knowledge about the vast majority of non-coding RNAs is still lacking. Here we identified long non-coding RNA (lncRNA) SPINT1-AS1 as a novel cervical cancer-associated lncRNA. SPINT1-AS1 was increased in cervical cancer and correlated with advanced stage and poor prognosis. SPINT1-AS1 was a direct downstream target of miR-214, a well-known tumor suppressive microRNA (miRNA) in cervical cancer. Intriguingly, SPINT1-AS1 was also found to repress miR-214 biogenesis via binding DNM3OS, the primary transcript of miR-214. The interaction between SPINT1-AS1 and DNM3OS repressed the binding of DROSHA and DGCR8 to DNM3OS, blocked DNM3OS cleavage, and therefore repressed mature miR-214 biogenesis. The expression of SPINT1-AS1 was significantly negatively correlated with miR-214 in cervical cancer tissues, supporting the reciprocal repression between SPINT1-AS1 and miR-214 in vivo. Through downregulating mature miR-214 level, SPINT1-AS1 upregulated the expression of β-catenin, a target of miR-214. Thus, SPINT1-AS1 further activated Wnt/β-catenin signaling in cervical cancer. Functionally, SPINT1-AS1 drove cervical cancer cellular proliferation, migration, and invasion in vitro, and also tumorigenesis in vivo. Deletion of the region mediating the interaction between SPINT1-AS1 and DNM3OS, overexpression of miR-214, and inhibition of Wnt/β-catenin signaling all reversed the roles of SPINT1-AS1 in cervical cancer. Collectively, these findings identified SPINT1-AS1 as a novel cervical cancer-associated oncogenic lncRNA which represses miR-214 biogenesis and activates Wnt/β-catenin signaling, highlighting its potential as prognostic biomarker and therapeutic target for cervical cancer.
Highlights
Cervical cancer is the fourth most common and fourth leading cause of cancer-associated death in women, with 604,127 new cervical cancer cases and 341,831 new cervical cancer deaths in 2020 worldwide (Sung et al, 2021)
We predicted 209 long non-coding RNA (lncRNA) which may interact with miR-214 supported by Ago CLIP-seq data using ENCORI (The Encyclopedia of RNA Interactomes) (Song et al, 2019)
We hypothesized that the lncRNAs which regulate miR-214 or be regulated by miR-214 should be upregulated in cervical cancer
Summary
Cervical cancer is the fourth most common and fourth leading cause of cancer-associated death in women, with 604,127 new cervical cancer cases and 341,831 new cervical cancer deaths in 2020 worldwide (Sung et al, 2021). Many studies are struggling to reveal the molecular mechanisms underlying cervical cancer (Cerasuolo et al, 2020; Lourenco de Freitas et al, 2020). Apart from the canonical oncogenes and tumor suppressors involved in cervical cancer, high throughput transcriptomic sequencings have identified more non-coding RNAs (ncRNAs) with dysregulated expression in cervical cancer (Berger et al, 2018). The expressions and roles of miRNAs have been intensively investigated in cervical cancer (Chen et al, 2019; Zheng et al, 2019). Several previous reports, including ours, have revealed miR-214 as a down-regulated and tumor suppressive miRNA in cervical cancer (Song et al, 2019; Peng et al, 2020; Tornesello et al, 2020). The pre-miRNAs are exported to cytoplasm where they were cleaved by DICER to generate mature miRNAs (Spadotto et al, 2020; Uebbing et al, 2021). miR-214 is located in the DNM3OS transcript unit which gives rise to mature miR-214 (Qin et al, 2012; Savary et al, 2019)
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