Abstract
Accumulating evidences indicate that circular RNAs (circRNAs), a subclass of noncoding RNAs, play important role in regulating gene expression in eukaryotes. Hsa_circ_0046263 (circ-0046263) was found aberrantly expressed in nasopharyngeal carcinoma (NPC), but its role in tumor growth and metastasis remains largely unclear. Sanger sequencing, RNase R assay, and nucleic acid electrophoresis were conducted to verify the identification of circ-0046263. Nuclear separation and fluorescence in situ hybridization (FISH) assays were used to determine the localization of circ-004263. Dual luciferase reporter and RNA immunoprecipitation (RIP) were employed to confirm the binding of circ-0046263 with miR-133a-5p. Colony formation, proliferation, wound healing, transwell, western blot, and in vivo tumor growth and metastasis assays were performed to assess the roles of circ-0046263, miR-133a-5p, IGFBP3 and their interactions in NPC cells. Circ-0046263 was upregulated in both NPC cell lines and tissues. The in vitro functional studies revealed that knockdown of circ-0046263 inhibited the proliferation, invasion, and migration of NPC cells, whereas its overexpression produced the opposite result. In vivo experiments indicated that knockdown or overexpression of circ-0046263 attenuated or promoted tumor growth and metastasis, respectively. Mechanistically, circ-0046263 could act as a miRNA sponge to absorb miR-133a-5p and upregulate the expression of miRNA downstream target IGFBP3. In addition, miR-133a-5p inhibition or IGFBP3 overexpression could rescue the malignant behavior induced by circ-0046263 silencing. Finally, circ-0046263 plays a tumor-promoting role in NPC to enhance malignant behavior through the miR-133a-5p/IGFBP3 axis, which could be a potential target for NPC therapy.
Highlights
Nasopharyngeal carcinoma (NPC) is a malignant tumor that originates from the superior mucosal epithelium of the nasopharynx
We found that the expression level of circ-0046263 was consistently and significantly increased in NPC tumor tissues compared to the matched nontumor tissues. quantitative realtime PCR (qRT-PCR) shown that circ-0046263 expression was increased in various NPC cell lines compared with that in immortalized nasopharyngeal epithelial NP69 cells (Fig. 1a)
Increasing evidence indicates that circRNAs are dysregulated in multiple tumors and may be involved in epithelial–mesenchymal transition (EMT), metastasis, and tumorigenesis[6,19]
Summary
Nasopharyngeal carcinoma (NPC) is a malignant tumor that originates from the superior mucosal epithelium of the nasopharynx. It is characterized by unique geographic distribution and is primarily prevalent in east and southeast Asian, with the highest incidence in southeast China[1,2]. Radiation is the most common therapy for NPC. Local recurrence and distant metastasis are very common in advanced-stage patients with NPC4. It is estimated that more than 30% of patients of stages III and IV will develop local recurrence or distant metastasis within 5 years after receiving combined treatment[4,5]. Further understanding of the molecular mechanisms underlying NPC progression and metastasis and identifying potential therapeutic targets are of paramount importance
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