Long noncoding RNA ZNF667‐AS1 reduces tumor invasion and metastasis in cervical cancer by counteracting microRNA‐93‐3p‐dependent PEG3 downregulation

• Published in: Molecular oncology Vol. 13; no. 11; pp. 2375 - 2392
• Main Authors: Li, Yong‐Jie, Yang, Zhe, Wang, Yi‐Ying, Wang, Yue
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.11.2019; John Wiley and Sons Inc; Wiley
• Subjects: Antisense RNA; Cell cycle; Cell growth; Cervical cancer; Cervix; Chromosome 19; Chromosome 3; Cyclin D1; Gene expression; Human papillomavirus; invasion; Matrix metalloproteinase; Metalloproteinase; Metastases; metastasis; MicroRNAs; microRNA‐93‐3p; miRNA; paternally expressed gene 3; Peg3 protein; Reporter gene; Studies; Therapeutic applications; Tissue inhibitor of metalloproteinases; Tumorigenesis; zinc finger protein 667‐antisense RNA 1; Zinc finger proteins; paternally expressed gene 3; invasion; microRNA-93-3p; metastasis; cervical cancer; zinc finger protein 667-antisense RNA 1
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12565

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. Schematic diagram of the regulation of Zinc finger protein 667‐antisense RNA 1 (ZNF667‐AS1) in cervical cancer. ZNF667‐AS1 negatively regulated microRNA‐93‐3p expression by targeting paternally expressed gene 3 (PEG3), thereby restraining cell proliferation and EMT. PEG3 increased the expression of tissue inhibitor of metalloproteinases and p16 and further decreased the expression of matrix metalloproteinase‐2 and ‐9.