Abstract
Zinc finger protein 667‐antisense RNA 1 (ZNF667‐AS1), located on human chromosome 19q13.43, is a member of the C2H2 zinc finger protein family. Herein, we aimed to analyze the interactions between ZNF667‐AS1, microRNA‐93‐3p (miR‐93‐3p), and paternally expressed gene 3 (PEG3) and to explore their roles in the tumorigenesis of cervical cancer (CC). Differentially expressed long noncoding RNAs and miRNAs related to CC were determined using gene expression datasets sourced from the Gene Expression Omnibus database. Subsequently, the regulatory relationships between ZNF667‐AS1 and miR‐93‐3p and between miR‐93‐3p and PEG3 were identified using the dual‐luciferase reporter gene assay. In addition, the expression of miR‐93‐3p and ZNF667‐AS1 was up‐ or downregulated in CC cells (HeLa), in order to assess their effects on cell cycle distribution and cell invasion in vitro, and tumor growth and metastasis in vivo. MiR‐93‐3p was found to be highly expressed, while ZNF667‐AS1 and PEG3 were poorly expressed in CC. ZNF667‐AS1 could competitively bind to miR‐93‐3p, which targeted PEG3. In addition, miR‐93‐3p downregulation and ZNF667‐AS1 overexpression led to increased expression of PEG3, tissue inhibitor of metalloproteinases, and p16 and decreased expression of cyclin D1, matrix metalloproteinase‐2 and ‐9. MiR‐93‐3p inhibition and ZNF667‐AS1 elevation also inhibited cell cycle entry and cell invasion in vitro, but repressed tumor growth and metastasis in vivo. These key findings demonstrated that upregulation of ZNF667‐AS1 could suppress the progression of CC via the modulation of miR‐93‐3p‐dependent PEG3, suggesting a potential therapeutic target for the treatment of CC.
Highlights
Cervical cancer (CC) has been ranked as the second leading cause of cancer-induced mortality in women worldwide; the incidence of CC is predominantly in developing countries where access to high-quality healthcare systems that facilitate timely screening that facilitates early diagnosis of CC may be limited (Berman and Schiller, 2017). Another serious concern is that the overall rate of 5-year survival for CC is Abbreviations CC, cervical cancer; GEO, Gene Expression Omnibus; HPV, human papillomavirus; Long noncoding RNAs (lncRNAs), long noncoding RNAs; miR-93-3p, microRNA93-3p; matrix metallopeptidase (MMP)-2, matrix metalloproteinase-2; MMP-9, matrix metalloproteinase-9; mRNAs, messenger RNAs; Mut, mutant type; NC, negative control; PEG3, paternally expressed gene 3; Propidium iodide (PI), propidium iodide; RT/qPCR, reverse transcription/quantitative PCR; TIMP-2, tissue inhibitor of metalloproteinases-2; Wt, wild type; Zinc finger protein 667 (ZNF667)-AS1, zinc finger protein 667-antisense RNA 1
In order to identify lncRNAs that are differentially expressed in CC, we performed a comprehensive lncRNA profiling analysis using the GEO datasets (GSE27678, GSE63514, GSE63678, and GSE9750)
These results signified that ZNF667-AS1 and PEG3 were poorly expressed, while miR-93-3p was highly expressed in CC affected tissues
Summary
Cervical cancer (CC) has been ranked as the second leading cause of cancer-induced mortality in women worldwide; the incidence of CC is predominantly in developing countries where access to high-quality healthcare systems that facilitate timely screening that facilitates early diagnosis of CC may be limited (Berman and Schiller, 2017).
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