Abstract
BackgroundCircular RNAs (circRNAs), a new type of noncoding RNA (ncRNA), have been identified as significant gene expression regulators and are involved in cancer progression. However, the roles of circRNAs in nasopharyngeal carcinoma (NPC) remain largely unknown.MethodsHere, the expression profile of circRNAs in a pair of NPC cell lines with different metastatic abilities (S18 and S26 cells) was analyzed by RNA-sequencing. Quantitative reverse transcription PCR was used to detect the expression level of circCRIM1 in NPC cells and tissues. Then, function experiments in vitro and in vivo were performed to evaluate the effects of circCRIM1 on NPC metastasis and EMT. Mechanistically, RNA immunoprecipitation, luciferase reporter assay, pull-down assay with biotinylated miRNA, fluorescent in situ hybridization were performed to confirm the interaction between circCRIM1 and miR-422a in NPC. The clinical value of circCRIM1 was evaluated in NPC metastasis and chemosensitivity.ResultsWe identified that circCRIM1 was upregulated in highly metastatic NPC cells. CircCRIM1 was also overexpressed in NPC tissues with distant metastasis, and its overexpression promoted NPC cell metastasis and EMT. Mechanistically, circCRIM1 competitively bound to miR-422a and prevented the suppressive effects of miR-422a on its target gene FOXQ1, which finally led to NPC metastasis, EMT and docetaxel chemoresistance. Furthermore, high circCRIM1 expression was associated with unfavorable survival in NPC patients. We established a prognostic model based on circCRIM1 expression and N stage that effectively predicted the risk of distant metastasis and treatment response to docetaxel-containing induction chemotherapy in NPC patients.ConclusionsOur findings reveal the critical role of circCRIM1 specifically in promoting NPC metastasis and chemoresistance via a ceRNA mechanism and provide an exploitable biomarker and therapeutic target for prognosis and treatment resistance in NPC patients.
Highlights
Nasopharyngeal carcinoma (NPC), which arises from the nasopharynx epithelium, is prevalent in Southeast Asia, North Africa, the Middle East and Alaska [1, 2]
CircRNA CRIM1 is upregulated in nasopharyngeal carcinoma (NPC) patients with distant metastasis To investigate metastasis-associated circRNAs in NPC, we performed an RNA sequencing analysis of ribosomal RNA-depleted and RNase-R-treated RNA from a pair of NPC cell lines with different metastatic abilities (S18 cells with high metastasis potential and S26 cells with low metastasis potential)
By mapping the human reference genome (GRCh37/hg19), we identified that hsa_circ_0002346 is derived from exons 2, 3 and 4 of the CRIM1 gene, which is located on chromosome 2p22.2
Summary
Nasopharyngeal carcinoma (NPC), which arises from the nasopharynx epithelium, is prevalent in Southeast Asia, North Africa, the Middle East and Alaska [1, 2]. According to the NCCN guidelines, radiotherapy combined with chemotherapy is the primary treatment strategy for locoregionally advanced NPC (LA-NPC) and substantially reduces locally recurrent disease [5]. CircRNAs have been identified to be dysregulated in different types of cancers [14,15,16,17]. CircRNAs can function as competitive endogenous RNAs (ceRNAs) or protein-coding RNAs or interact with RNA-binding proteins to regulate the expression of genes involved in tumorigenesis and progression [14, 15, 17]. The functions and mechanisms of circRNAs remain to be elucidated in NPC. Circular RNAs (circRNAs), a new type of noncoding RNA (ncRNA), have been identified as significant gene expression regulators and are involved in cancer progression. The roles of circRNAs in nasopharyngeal carcinoma (NPC) remain largely unknown
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