Circular RNA hsa_circ_0001666 sponges miR-330-5p, miR-193a-5p and miR-326, and promotes papillary thyroid carcinoma progression via upregulation of ETV4

Abstract

Circular RNAs (circRNAs) are a group of regulators that affect the aggressive behaviors of several types of cancer. Hsa_circ_0001666 (also referred to as hsa_circ_000742) is a newly discovered circRNA that is upregulated in human papillary thyroid carcinoma (PTC) based on microarray analysis. However, the role of hsa_circ_0001666 in PTC progression remains unknown. Thus, the aim of the present study was to determine the potential function and under- lying mechanism of hsa_circ_0001666 in PTC. The results demonstrated that hsa_circ_0001666 was upregulated in both PTC clinical samples and cell lines. Its expression was associated with lymph node metastasis of patients with PTC. Knocking down hsa_circ_0001666 expression inhibited cell proliferation, as evidenced by decreased cell viability, arrest of cell cycle progression at the G1 phase and an increase in cell cycle-associated proteins. Apoptosis rates and expression levels of pro-apoptotic proteins were also increased by silencing hsa_circ_0001666. In xenograft experiments, the oncogenic effect of hsa_circ_0001666 on tumor growth was verified. Additionally, luciferase reporter assays showed that hsa_circ_0001666 and ETS variant transcription factor 4 (ETV4) shared common binding sites with three microRNAs [(miRNA/miR)-330-5p, miR-193a-5p and miR-326]. Knockdown of these miRNAs separately reversed the inhibitory effect of hsa_circ_0001666 small interfering RNAs on PTC tumor aggressiveness, and ETV4 overexpression also induced a similar effect to that of miRNA inhibitors. Thus, hsa_circ_0001666 may function as an oncogene, promoting PTC tumorigenesis via the miR-330-5p/miR-193a-5p/miR-326/ETV4 pathway. This provides a basis for identifying potential novel therapeutic targets for PTC.