Search

Nasopharyngeal carcinoma (NPC) is a common malignant tumor of the head and neck, prevalent in regions such as Southern China and Southeast Asia. Radiotherapy serves as the primary clinical treatment for this carcinoma. However, resistance to radiotherapy is a fundamental cause of treatment failure and patient mortality, with the underlying mechanisms yet to be fully elucidated. We identified a recently characterized circular RNA, circADARB1, which is markedly upregulated in NPC tissues and closely associated with poor prognosis and radiotherapy resistance. Both in vitro and in vivo experiments demonstrated that circADARB1 inhibited ferroptosis, thereby inducing radiotherapy resistance in NPC cells. Building on these findings, we synthesized a biomimetic nanomaterial consisting of semiconducting polymer nanoparticles wrapped in cell membranes, designed to deliver both siRNA targeting circADARB1 and iron ions. The application of this nanomaterial not only efficiently suppressed the expression of circADARB1 and boosted intracellular iron concentrations, but also enhanced ferroptosis induced by radiotherapy, improving the radiosensitivity of NPC cells. Furthermore, our study revealed that circADARB1 upregulated the expression of heat shock protein HSP90B1, which repaired misfolded SLC7A11 and GPX4 proteins triggered by radiotherapy, thereby preserving their stability and biological functions. Mechanistically, SLC7A11 facilitated cysteine transportation into cells and glutathione synthesis, while GPX4 employed glutathione to mitigate intracellular lipid peroxidation induced by radiotherapy, shielding cells from oxidative damage and inhibiting ferroptosis, and ultimately leading to radiotherapy resistance in NPC cells. Our investigation elucidates molecular mechanisms with substantial clinical relevance, highlights the promising application prospects of nanotechnology in precision cancer therapy.

Background: N 6 -methyladenosine (m 6 A) modification is essential for modulating RNA processing as well as expression, particularly in the context of malignant tumour progression. However, the exploration of m 6 A modification in nasopharyngeal carcinoma (NPC) remains very limited., Methods: RNA m 6 A levels were analysed in NPC using m 6 A dot blot assay. The expression level of methyltransferase-like 14 (METTL14) within NPC tissues was analysed from public databases as well as RT-qPCR and immunohistochemistry. The influences on METTL14 expression on NPC proliferation and metastasis were explored via in vitro as well as in vivo functional assays. Targeted genes of METTL14 were screened using the m 6 A and gene expression profiling microarray data. Actinomycin D treatment and polysome analysis were used to detect the half-life and translational efficiency of ANKRD22. Flow cytometry, immunofluorescence and immunoprecipitation were used to validate the role of ANKRD22 on lipid metabolism in NPC cells. ChIP-qPCR analysis of H3K27AC signalling near the promoters of METTL14, GINS3, POLE2, PLEK2 and FERMT1 genes., Results: We revealed METTL14, in NPC, correlating with poor patient prognosis. In vitro and in vivo assays indicated METTL14 actively promoted NPC cells proliferation and metastasis. METTL14 catalysed m 6 A modification on ANKRD22 messenger ribonucleic acid (mRNA), recognized by the reader IGF2BP2, leading to increased mRNA stability and higher translational efficiency. Moreover, ANKRD22, a metabolism-related protein on mitochondria, interacted with SLC25A1 to enhance citrate transport, elevating intracellular acetyl-CoA content. This dual impact of ANKRD22 promoted lipid metabolism reprogramming and cellular lipid synthesis while upregulating the expression of genes associated with the cell cycle (GINS3 and POLE2) and the cytoskeleton (PLEK2 and FERMT1) through heightened epigenetic histone acetylation levels in the nucleus. Intriguingly, our findings highlighted elevated ANKRD22-mediated histone H3 lysine 27 acetylation (H3K27AC) signals near the METTL14 promoter, which contributes to a positive feedback loop perpetuating malignant progression in NPC., Conclusions: The identified METTL14-ANKRD22-SLC25A1 axis emerges as a promising therapeutic target for NPC, and also these molecules may serve as novel diagnostic biomarkers., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Circular RNAs (circRNAs) play an important regulatory role in the pathogenesis and progression of nasopharyngeal carcinoma (NPC), which have not been thoroughly elucidated. In this study, we revealed for the first time that circRILPL1 was upregulated in NPC, weakened adhesion and decreased stiffness of NPC cells, and promoted NPC proliferation and metastasis in vitro and in vivo. Mechanistically, circRILPL1 inhibited the LATS1-YAP kinase cascade by binding to and activating ROCK1, resulting in decrease of YAP phosphorylation. Binding and cooperating with transport receptor IPO7, circRILPL1 promoted the translocation of YAP from the cytoplasm to the nucleus, where YAP enhanced the transcription of cytoskeleton remodeling genes CAPN2 and PXN. By which, circRILPL1 contributed to the pathogenesis of NPC. Our results demonstrated that circRILPL1 promoted the proliferation and metastasis of NPC through activating the Hippo-YAP signaling pathway by binding to both ROCK1 and IPO7. Highly expressed circRILPL1 in NPC may serve as an important biomarker for tumor diagnosis and may also be a potential therapeutic target., (© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Nasopharyngeal carcinoma (NPC) is a malignant tumor that usually occurs in people from Southeast Asia and Southern China. NPC is prone to migration and invasion, leading to poor prognosis. A large number of circular RNAs (circRNAs) exacerbate the process of metastasis in NPC; however, their underlying mechanisms remain unclear. We found that the circular RNA circCCNB1, encoded by the oncogene CCNB1, was downregulated in NPC biopsies and cell lines. In vitro assays show that circCCNB1 inhibits NPC cell migration and invasion. Moreover, circCCNB1 induces a protein, nuclear factor 90 (NF90), to bind and prolong the half-life of tight junction protein 1 (TJP1) mRNA. Upregulation of TJP1 enhances tight junctions between cancer cells and inhibits NPC cell migration and invasion. This study reveals a novel biological function of circCCNB1 in the migration and invasion of NPC by enhancing the tight junctions of cancer cells by binding to NF90 proteins and TJP1 mRNA, and may provide a potential therapeutic target for NPC., (© 2022. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Circular RNAs (circRNAs) act as gene expression regulators and are involved in cancer progression. However, their functions have not been sufficiently investigated in nasopharyngeal carcinoma (NPC)., Methods: The expression profiles of circRNAs in NPC cells within different metastatic potential were reanalyzed. Quantitative reverse transcription PCR and in situ hybridization were used to detect the expression level of circPVT1 in NPC cells and tissue samples. The association of expression level of circPVT1 with clinical properties of NPC patients was evaluated. Then, the effects of circPVT1 expression on NPC metastasis were investigated by in vitro and in vivo functional experiments. RNA immunoprecipitation, pull-down assay and western blotting were performed to confirm the interaction between circPVT1 and β-TrCP in NPC cells. Co-immunoprecipitation and western blotting were performed to confirm the interaction between β-TrCP and c-Myc in NPC cells., Results: We find that circPVT1, a circular RNA, is significantly upregulated in NPC cells and tissue specimens. In vitro and in vivo experiments showed that circPVT1 promotes the invasion and metastasis of NPC cells. Mechanistically, circPVT1 inhibits proteasomal degradation of c-Myc by binding to β-TrCP, an E3 ubiquiting ligase. Stablization of c-Myc by circPVT1 alters the cytoskeleton remodeling and cell adhesion in NPC, which ultimately promotes the invasion and metastasis of NPC cells. Furthermore, c-Myc transcriptionally upregulates the expression of SRSF1, an RNA splicing factor, and recruits SRSF1 to enhance the biosynthesis of circPVT1 through coupling transcription with splicing, which forms a positive feedback for circPVT1 production., Conclusions: Our results revealed the important role of circPVT1 in the progression of NPC through the β-TrCP/c-Myc/SRSF1 positive feedback loop, and circPVT1 may serve as a prognostic biomarker or therapeutic target in patients with NPC., (© 2022. The Author(s).)

Background: Circular RNAs play an important role in tumor genesis and progression, but they have not been sufficiently studied in patients with nasopharyngeal carcinoma (NPC)., Methods: The circular RNA, circCAMSAP1, was screened in NPC cells by RNA sequencing analysis. The expression of circCAMSAP1 in NPC tissues was examined by real-time quantitative polymerase chain reaction (RT-qPCR) and in situ hybridization. Wound-healing, transwell, MTT and flow cytometry assays, and nude mouse tumor models were used to explore the effect of circCAMSAP1 on proliferation and metastasis of NPC in vitro or in vivo. The downstream proteins regulated by circCAMSAP1 were screened using mass spectrometry. The interaction between circCAMSAP1 and the SERPINH1 mRNA was identified using the circular RNA immunoprecipitation method and the luciferase reporter assay. The interaction between SERPINH1 and transcription factor c-Myc was verified through Co-immunoprecipitation (Co-IP) and immunofluorescence. The effect of c-Myc on the generation of circCAMSAP1 was examined through RT-qPCR and chromatin immunoprecipitation. Finally, the splicing factors that promote the production of circCAMSAP1 were explored by RT-qPCR and RNA immunoprecipitation (RIP)., Results: We found that circCAMSAP1 was highly expressed in NPC tissues and promoted NPC proliferation and metastasis. Additionally, circCAMSAP1 promoted SERPINH1 expression through improved SERPINH1 mRNA stability by binding to the 3'-untranslated region (3'UTR) of SERPINH1. Highly expressed SERPINH1 reduced the ubiquitination-degradation rate of c-Myc, causing increased tumorigenesis. Meanwhile, c-Myc, cooperating with splicing factor 10 (SRSF10), could also promote CAMSAP1 pre-mRNA transcription and back-splicing, forming a positive feedback of circCAMSAP1 production, resulting in the proliferation and metastasis of NPC., Conclusions: Our findings revealed that circCAMSAP1 promotes NPC proliferation and metastasis by binding to the 3'UTR of SERPINH1, suggesting that the positive feedback of circCAMSAP1-SERPINH1-c-Myc may serve as a prognostic biomarker or therapeutic target in patients with NPC., (© 2022. The Author(s).)

Nasopharyngeal carcinoma (NPC) demonstrates significant regional differences and a high incidence in Southeast Asia and Southern China. Bactericidal/permeability-increasing-fold- containing family B member 1 (BPIFB1) is a relatively specific and highly expressed protein in the nasopharyngeal epithelium. BPIFB1 expression is substantially downregulated in NPC and is significantly associated with poor prognosis in patients with NPC. However, the specific molecular mechanism by which BPIFB1 regulates NPC is not well understood. In this study, we found that BPIFB1 inhibits vasculogenic mimicry by regulating the metabolic reprogramming of NPC. BPIFB1 decreases GLUT1 transcription by downregulating the JNK/AP1 signaling pathway. Altered glycolysis reduces the acetylation level of histone and decreases the expression of vasculogenic mimicry-related genes, VEGFA, VE-cadherin, and MMP2, ultimately leading to the inhibition of vasculogenic mimicry. To our knowledge, this is the first report on the role and specific mechanism of BPIFB1 as a tumor suppressor gene involved in regulating glycolysis and vasculogenic mimicry in NPC. Overall, these results provide a new therapeutic target for NPC diagnosis and treatment., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Gossypol has been reported to exhibit antitumor effects against several human cancers. However, the anticancer effects of gossypol on nasopharyngeal carcinoma (NPC) have not been investigated. Against this backdrop, the present study was designed to evaluate the anticancer effects of gossypol against NPC cells and to identify the signaling pathways involved through bioinformatic analysis. Gossypol-inhibited death of NPC cells is concentration-dependent. To explore the underlying mechanism for gossypol's antitumor effect, microarray of gossypol-treated and -untreated NPC cells was performed. A total of 836 differentially expressing genes (DEGs) were identified in gossypol-treated NPC cells, of which 461 genes were upregulated and 375 genes were downregulated. The cellular components, molecular functions, biological processes, and signal pathways, in which the DEGs were involved, were identified by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The Gene Set Enrichment Analysis (GSEA) predicted upstream transcription factors (TF) ETS2 and E2F1 that regulate DEGs. Weighted Gene Co-expression Network Analysis (WGCNA) was performed to identify a class of modules and genes related to DNA repair and cell cycle. TNFRSF10B , a receptor for death in NPC cells, was knocked down. The results suggested that the ability of NPC cells to resist gossypol killing was enhanced. In addition, to further investigate the possible molecular mechanisms, we constructed a transcriptional regulatory network of TNFRSF10B containing 109 miRNAs and 47 TFs. Taken together, our results demonstrated that gossypol triggered antitumor effects against NPC cells, indicating its applicability for the management of NPC.

Circular RNAs (circRNAs) play an essential role in tumorigenesis and development. However, they have rarely been investigated in nasopharyngeal carcinoma (NPC). This study aimed to investigate the role of circRNA in the invasion and metastasis of NPC. We screened and verified the high expression of circSETD3 in NPC cell lines using RNA sequencing (RNA-Seq) and verified the results of NPC biopsy samples using real-time quantitative polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH). In vivo and in vitro experiments indicated that circSETD3 could promote NPC cell invasion and migration. We compared the proteomic data of NPC cells before and after the overexpression or knockdown of circSETD3 in combination with bioinformatics prediction and experimental verification. It was found that circSETD3 competitively adsorbs to miR-615-5p and miR-1538 and negates their inhibitory effect on MAPRE1 mRNA, thereby upregulating the expression of MAPRE1. The upregulated MAPRE1 then inhibits the acetylation of α-tubulin, promotes the dynamic assembly of microtubules, and enhances the invasion and migration capabilities of NPC cells. The results of this study suggest that circSETD3 is a novel molecular marker and a potential target for NPC diagnosis and treatment.

An increasing number of studies have shown that circular RNAs (circRNAs) play important roles in malignant tumor initiation and progression; however, many circRNAs are yet unidentified, and the role of circRNAs in nasopharyngeal carcinoma (NPC) is unclear. Using RNA sequencing, we discovered a novel circRNA, termed circARHGAP12, that was processed from the pre-mRNA of the ARHGAP12 gene. CircARHGAP12 was significantly upregulated in NPC tissues and cell lines and promoted NPC cell migration and invasion. Overexpression or knockdown experiments revealed that circARHGAP12 regulates the expression of cytoskeletal remodeling-related proteins EZR, TPM3, and RhoA. CircARHGAP12 was found to bind directly to the 3' UTR of EZR mRNA and promote its stability; moreover, EZR protein interacted with TPM3 and RhoA and formed a complex to promote NPC cell invasion and metastasis. This study identified the novel circRNA circARHGAP12, characterized its biological function and mechanism, and increased our understanding of circRNAs in NPC pathogenesis. In particular, circARHGAP12 was found to promote the malignant biological phenotype of NPC via cytoskeletal remodeling, thus providing a clue for targeted therapy of NPC., (Copyright © 2020 Elsevier B.V. All rights reserved.)