Abstract
BackgroundDespite a good and overall prognosis, papillary thyroid cancer (PTC) can still affect the quality of life of many patients, and can even be life-threatening due to its invasiveness and metastasis. Emerging studies demonstrate that circular RNAs (circRNAs) participate in the regulation of various cancers. However, the circRNA profile in invasive PTC is still not well understood.MethodsCompeting endogenous RNA (ceRNA) microarrays were performed to determine circRNAs contributed to the tumorigenesis and invasiveness of PTC. Bioinformatics methods were used to narrow down the candidate circRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) assays revealed a significant upregulation of hsa_circ_0058124 in PTC tissue and a close correlation with a poor prognosis for PTC patients. RNA fluorescence in situ hybridization and Cell fractionation assay were used to investigate the subcellular location of hsa_circ_0058124. Then, we examined the functions of hsa_circ_0058124 in PTC by cell proliferation, cell cycle, apoptosis, migration and invasion assay. Mechanistically, RNA sequencing and GSEA analysis were applied to predict the downstream pathway of hsa_circ_0058124. Dual-luciferase report assays were used to explore the potential miRNA sponge role of hsa_circ_0058124. Western blotting, cell proliferation, cell cycle, cell apoptosis, migration and invasion, and mouse xenograft assay were used to validate the effects of hsa_circ_0058124/NOTCH3/GATAD2A axis on PTC progression.ResultsIn the current study, a novel hsa_circ_0058124 on 2q35 was identified and explored in PTC. Hsa_circ_0058124 is associated with the malignant features and poor outcomes of PTC patients. Hsa_circ_0058124 acts as an oncogenic driver that promotes PTC cell proliferation, tumorigenicity, tumor invasion, and metastasis, which functions as a competing endogenous RNA to modulate miRNA-218-5p and its target gene NUMB expression, and consequently with repression of the NOTCH3/GATAD2A signaling axis in vitro and in vivo.ConclusionsThis study unveils a novel biomarker panel consisting of the hsa_circ_0058124/NOTCH3/GATAD2A axis which is critical for PTC tumorigenesis and invasiveness and may represent a novel therapeutic target for intervening in PTC progression.
Highlights
Despite a good and overall prognosis, papillary thyroid cancer (PTC) can still affect the quality of life of many patients, and can even be life-threatening due to its invasiveness and metastasis
The results revealed a novel biomarker panel consisting of the hsa_circ_0058124/NOTCH3/GATAD2A axis that is critical in PTC tumorigenesis and invasiveness and may be a novel therapeutic target to intervene PTC progression
The quantitative real-time PCR (qRTPCR) results indicated hsa_circ_0058124 showed highest fold-change in the PTC tissues than in the control tissues, and was significantly upregulated in the invasive PTC tissues compared with non-invasive tumor tissues (Additional file 2: Figure S2)
Summary
Despite a good and overall prognosis, papillary thyroid cancer (PTC) can still affect the quality of life of many patients, and can even be life-threatening due to its invasiveness and metastasis. Thyroid cancer (TC) is the most prevalent endocrine malignancy in the world, and its incidence has ascended steadily over the past decades [1]. Despite its overall good prognosis, PTC can still affect the quality of life of many patients and can even become lifethreatening due to invasiveness and metastasis [5, 6]. Extrathyroidal extension (ETE) has long been recognized as an independent predictor of poor outcome in patients with PTC Does such invasive disease result in higher rates of recurrence, but 5-year survival rate is compromised in this patient group [8,9,10]. This poor clinical prognosis of invasive PTC emphasizes the urgency of exploring the mechanism of invasive PTC and developing novel anticancer agents that could intervene in PTC progression
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