Abstract
nc886 or VRNA2-1 has recently been identified as a noncoding RNA instead of a vault RNA or a pre-microRNA. Several studies have reported that pre-miR-886 plays a tumor-suppressive role in a wide range of cancer cells through its activity as a cellular protein kinase RNA-activated (PKR) ligand and repressor. However, by sequencing stem-PCR products, we found that a microRNA originating from this precursor, vault RNA2-1-5p (VTRNA2-1-5p), occurs in cervical cancer cells. The expression levels of the predicted targets of VTRNA2-1-5p are negatively correlated with VTRNA2-1-5p levels by quantitative reversion transcription PCR (qRT-PCR). Previous results have shown that VTRNA2-1-5p is overexpressed in human cervical squamous cell carcinomas (CSCCs) compared with adjacent healthy tissues. Inhibition of VTRNA2-1-5p increases Bax protein expression and apoptotic cell death in cervical cancer cells. Our findings suggest that VTRNA2-1-5p has oncogenic activity related to the progression of cervical cancer. Here, we report that VTRNA2-1-5p directly targeted p53 expression and functioned as an oncomir in cervical cancer. VTRNA2-1-5p inhibition decreased cervical cancer cell invasion, proliferation, and tumorigenicity while increasing apoptosis and p53 expression. Interestingly, VTRNA2-1-5p inhibition also increased cisplatin-induced apoptosis of HeLa and SiHa cells. In human clinical cervical cancer specimens, low p53 expression and high VTRNA2-1-5p expression were positively associated.In addition, VTRNA2-1-5p was found to directly target the 5' and 3' untranslated regions (UTRs) of p53. We propose that VTRNA2-1-5p is a direct regulator of p53 and suggest that it plays an essential role in the apoptosis and proliferation of cervical cancer cells.
Highlights
Cervical cancer is the second-most common cancer in women, and the integration of human papillomavirus (HPV) DNA into the host genome is a typical, not exclusive, step in cervical carcinogenesis [1, 2]
Because VTRNA2-1-5p occurs in the cell and VTRNA2-1 can be processed into mature VTRNA21-5p, changes in the VTRNA2-1-5p level should impact the level of VTRNA2-1
Consistent with our predictions, VTRNA2-1-5p inhibitors significantly down-regulated the level of VTRNA2-1 (p < 0.05), whereas exposure of the cells to VTRNA2-1-5p mimics did not impact the level of VTRNA2-1 (p > 0.05, Figure 1F), which was highly abundant (~105 molecules per cell) in HeLa
Summary
Cervical cancer is the second-most common cancer in women, and the integration of human papillomavirus (HPV) DNA into the host genome is a typical, not exclusive, step in cervical carcinogenesis [1, 2]. In a previous investigation of miRNAs that are differentially expressed in cervical squamous cell carcinoma (CSCC) and adjacent healthy tissue, we found that miR-886-5p is highly overexpressed in cancerous tissue. Experimental evidence suggests that miR-886 is not a canonical miRNA but a vault RNA (VTRNA) because the sequence alignments clearly identify this sequence as a VTRNA homolog or a molecule associated with the vault complex [9, 10]. Lee et al provided solid experimental evidence that pre-miR-886 is neither a VTRNA nor a canonical miRNA, they could not rule out the possibility that only a minute amount of pre-miR-886 is associated with major vault protein (MVP) and has a biological function [11]. Despite the divergence in the characterization of pre-miR-886, all the available data are consistent in suggesting that human VTRNAs are RNA polymerase III (Pol III) transcripts with defective stemloop secondary structures
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