RESUMEN
Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15â¯% of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC.
Asunto(s)
ARN Helicasas DEAD-box , Desoxicitidina , Gemcitabina , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , ARN Largo no Codificante , Animales , Humanos , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ARN Helicasas DEAD-box/metabolismo , ARN Helicasas DEAD-box/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/metabolismo , Proteínas de Neoplasias , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Ubiquitinación/efectos de los fármacosRESUMEN
In a recently published phase III clinical trial, gemcitabine (GEM) plus cisplatin (DDP) induction chemotherapy significantly improved recurrence-free survival and overall survival and became the standard of care among patients with locoregionally advanced NPC. However, the molecular mechanisms of GEM synergized with DPP in NPC cells remain elucidated. These findings prompt us to explore the effect of the combination between GEM and DDP in NPC cell lines through proliferative phenotype, immunofluorescence, flow cytometry, and western blotting assays. In vitro studies reveal that GEM or DPP treated alone induces cell cycle arrest, promotes cell apoptosis, forces DNA damage response, and GEM synergism with DDP significantly increases the above effects in NPC cells. In vivo studies indicate that GEM or DPP treated alone significantly inhibits the tumor growth and prolongs the survival time of mice injected with SUNE1 cells compared to the control group. Moreover, the mice treated with GEM combined with DDP have smaller tumors and survive longer than those in GEM or DPP treated alone group. In addition, P-gp may be the key molecule that regulates the synergistic effect of gemcitabine and cisplatin. GEM synergizes with DPP to inhibit NPC cell proliferation and tumor growth by inducing cell cycle arrest, cell apoptosis, and DNA damage response, which reveals the mechanisms of combined GEM and DDP induction chemotherapy in improving locoregionally advanced NPC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proliferación Celular/efectos de los fármacos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Cisplatino/agonistas , Cisplatino/farmacología , Desoxicitidina/agonistas , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Sinergismo Farmacológico , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
Alternative polyadenylation (APA), which induces shortening of the 3'-UTR, is emerging as an important feature in cancer development and progression. Nevertheless, the effects and mechanisms of APA-induced 3'-UTR shortening in nasopharyngeal carcinoma (NPC) remain largely unclear. Fibronectin type III domain containing 3B (FNDC3B) tended to use proximal polyadenylation site and produce shorter 3'-UTR according to our previous sequencing study. Herein, we found that FNDC3B with shorter 3'-UTR could escape from miRNA-mediated gene repression, and caused its increased expression in NPC. Knocking down of FNDC3B inhibited NPC cell proliferation, migration, invasion, and metastasis in vitro and in vivo. Overexpression of FNDC3B, especially those with shorter 3'-UTR, promoted NPC progression. Furthermore, the mechanism study revealed that FNDC3B could bind to and stabilize myosin heavy chain 9 (MYH9) to activate the Wnt/ß-catenin signaling pathway. In addition, MYH9 could reverse the inhibitory effects of FNDC3B knockdown in NPC. Altogether, our results suggested that the 3'-UTR shortening of FNDC3B mRNA mediated its overexpression in NPC and promoted NPC progression by targeting MYH9. This newly identified FNDC3B-MYH9-Wnt/ß-catenin axis could represent potential targets for individualized treatment in NPC.
Asunto(s)
Fibronectinas/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Cadenas Pesadas de Miosina/metabolismo , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/patología , Regiones no Traducidas 3' , Animales , Movimiento Celular/genética , Proliferación Celular/genética , Progresión de la Enfermedad , Fibronectinas/genética , Xenoinjertos , Humanos , Ratones , MicroARNs , Cadenas Pesadas de Miosina/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Vía de Señalización Wnt/fisiologíaRESUMEN
OBJECTIVES: In the current era, clinicians working in areas with limited and/or without facilities are only able to manage their patients based on clinical signs to detect dysphagia. This study assesses the performance of 5 simple clinical signs for predicting the severity of dysphagia. METHODS: We systematically documented 5 targeted bedside clinical signs within 24 h after admission in 737 consecutive patients with acute stroke. We examined the median onset of each sign and calculated their ratios associated with severe dysphagia. The performance and significance of these special clinical signs were evaluated by further computation. RESULTS: In total, 184 of 737 AIS patients were screened positive dysphagia by the modified V-VST. The 5 targeted bedside clinical signs were differed among the patients with and without dysphagia. Patients with serious dysphagia (n = 61,33.15%) showed higher positive percentages of larynx movement disorders than those classified as moderate (73.77% [60.99%-83.50%] vs 29.27% [21.82%-38.03%], p < 0.001). Logistic regression analyses conducted in the subsets confirmed larynx movement disorders as an independent predictor of dysphagia severity. CONCLUSIONS: Larynx movement disorders is correlated with a higher probability of severe dysphagia as measured by the modified V-VST in AIS patients.
Asunto(s)
Trastornos de Deglución , Accidente Cerebrovascular Isquémico , Trastornos del Movimiento , Accidente Cerebrovascular , Humanos , Trastornos de Deglución/etiología , Trastornos de Deglución/complicaciones , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , HospitalizaciónRESUMEN
BACKGROUND: Metastasis has emerged as the major reason of treatment failure and mortality in patients with nasopharyngeal carcinoma (NPC). Growing evidence links abnormal DNA methylation to the initiation and progression of NPC. However, the precise regulatory mechanism behind these processes remains poorly understood. METHODS: Bisulfite pyrosequencing, RT-qPCR, western blot, and immunohistochemistry were used to test the methylation and expression level of NEURL3 and its clinical significance. The biological function of NEURL3 was examined both in vitro and in vivo. Mass spectrometry, co-immunohistochemistry, immunofluorescence staining, and ubiquitin assays were performed to explore the regulatory mechanism of NEURL3. RESULTS: The promoter region of NEURL3, encoding an E3 ubiquitin ligase, was obviously hypermethylated, leading to its downregulated expression in NPC. Clinically, NPC patients with a low NEURL3 expression indicated an unfavorable prognosis and were prone to develop distant metastasis. Overexpression of NEURL3 could suppress the epithelial mesenchymal transition and metastasis of NPC cells in vitro and in vivo. Mechanistically, NEURL3 promoted Vimentin degradation by increasing its K48-linked polyubiquitination at lysine 97. Specifically, the restoration of Vimentin expression could fully reverse the tumor suppressive effect of NEURL3 overexpression in NPC cells. CONCLUSIONS: Collectively, our study uncovers a novel mechanism by which NEURL3 inhibits NPC metastasis, thereby providing a promising therapeutic target for NPC treatment.
Asunto(s)
Neoplasias Nasofaríngeas , Ubiquitina-Proteína Ligasas , Humanos , Carcinoma Nasofaríngeo/genética , Ubiquitina-Proteína Ligasas/genética , Vimentina/genética , Transición Epitelial-Mesenquimal , Neoplasias Nasofaríngeas/genéticaRESUMEN
Despite docetaxel combined with cisplatin and 5-fluorouracil (TPF) being the established treatment for advanced nasopharyngeal carcinoma (NPC), there are patients who do not respond positively to this form of therapy. However, the mechanisms underlying this lack of benefit remain unclear. DCAF7 is identified as a chemoresistance gene attenuating the response to TPF therapy in NPC patients. DCAF7 promotes the cisplatin resistance and metastasis of NPC cells in vitro and in vivo. Mechanistically, DCAF7 serves as a scaffold protein that facilitates the interaction between USP10 and G3BP1, leading to the elimination of K48-linked ubiquitin moieties from Lys76 of G3BP1. This process helps prevent the degradation of G3BP1 via the ubiquitinâproteasome pathway and promotes the formation of stress granule (SG)-like structures. Moreover, knockdown of G3BP1 successfully reversed the formation of SG-like structures and the oncogenic effects of DCAF7. Significantly, NPC patients with increased levels of DCAF7 showed a high risk of metastasis, and elevated DCAF7 levels are linked to an unfavorable prognosis. The study reveals DCAF7 as a crucial gene for cisplatin resistance and offers further understanding of how chemoresistance develops in NPC. The DCAF7-USP10-G3BP1 axis contains potential targets and biomarkers for NPC treatment.
RESUMEN
Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.
Asunto(s)
Docetaxel , Resistencia a Antineoplásicos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Piroptosis , Ubiquitina-Proteína Ligasas , Ubiquitinación , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Cisplatino/farmacología , Cisplatino/uso terapéutico , Docetaxel/farmacología , Docetaxel/uso terapéutico , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Dinaminas/metabolismo , Dinaminas/genética , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Gasderminas , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Fosfoproteínas Fosfatasas/metabolismo , Fosfoproteínas Fosfatasas/genética , Fosforilación/efectos de los fármacos , Piroptosis/efectos de los fármacos , Piroptosis/genética , Especies Reactivas de Oxígeno/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The dysregulation of long non-coding RNAs (lncRNAs) are involved in regulating tumor progression in multiple manner. However, little is known about whether lncRNA is involved in the translation regulation of proteins. Here, we identified that the suppressor of inflammatory macrophage apoptosis lncRNA (SIMALR) was highly expressed in nasopharyngeal carcinoma (NPC) tissues by analyzing the lncRNA microarray. Clinically, the high expression of SIMALR served as an independent predictor for inferior prognosis in NPC patients. SIMALR functioned as an oncogenic lncRNA that promoted the proliferation and metastasis of NPC cells in vitro and in vivo. Mechanistically, SIMALR served as a critical accelerator of protein synthesis by binding to eEF1A2 (eukaryotic translation elongation factor 1 alpha 2), one of the most crucial regulators in the translation machinery of the eukaryotic cells, and enhancing its endogenous GTPase activity. Furthermore, SIMALR mediated the activation of eEF1A2 phosphorylation to accelerate the translation of ITGB4/ITGA6, ultimately promoting the malignant phenotype of NPC cells. In addition, N-acetyltransferase 10 (NAT10) enhanced the stability of SIMALR and caused its overexpression in NPC through the N4-acetylcytidine (ac4C) modification. In sum, our results illustrate SIMALR functions as an accelerator for protein translation and highlight the oncogenic role of NAT10-SIMALR-eEF1A2-ITGB4/6 axis in NPC.
RESUMEN
Despite that the docectaxel-cisplatin-5-fluorouracil (TPF) induction chemotherapy has greatly improved patients' survival and became the first-line treatment for advanced nasopharyngeal carcinoma (NPC), not all patients could benefit from this therapy. The mechanism underlying the TPF chemoresistance remains unclear. Here, by analyzing gene-expression microarray data and survival of patients who received TPF chemotherapy, we identify transcription factor ATMIN as a chemoresistance gene in response to TPF chemotherapy in NPC. Mass spectrometry and Co-IP assays reveal that USP10 deubiquitinates and stabilizes ATMIN protein, resulting the high-ATMIN expression in NPC. Knockdown of ATMIN suppresses the cell proliferation and facilitates the docetaxel-sensitivity of NPC cells both in vitro and in vivo, while overexpression of ATMIN exerts the opposite effect. Mechanistically, ChIP-seq combined with RNA-seq analysis suggests that ATMIN is associated with the cell death signaling and identifies ten candidate target genes of ATMIN. We further confirm that ATMIN transcriptionally activates the downstream target gene LCK and stabilizes it to facilitate cell proliferation and docetaxel resistance. Taken together, our findings broaden the insight into the molecular mechanism of chemoresistance in NPC, and the USP10-ATMIN-LCK axis provides potential therapeutic targets for the management of NPC.
Asunto(s)
Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patología , Docetaxel/uso terapéutico , Neoplasias Nasofaríngeas/patología , Factores de Transcripción/uso terapéutico , Resistencia a Antineoplásicos , Fluorouracilo/uso terapéutico , Quimioradioterapia/métodos , Cisplatino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ubiquitina TiolesterasaRESUMEN
An increasing number of studies have found that long non-coding RNA (lncRNA) play important roles in driving the progression of nasopharyngeal carcinoma (NPC). Our microarray screening revealed that expression of the lncRNA long intergenic non-protein coding RNA 173 (LINC00173) was upregulated in NPC. However, its role and mechanism in NPC have not yet been elucidated. In this study, we demonstrate that high LINC00173 expression indicated a poor prognosis in NPC patients. Knockdown of LINC00173 significantly inhibited NPC cell proliferation, migration and invasion in vitro. Mechanistically, LINC00173 interacted and colocalized with Ras-related protein Rab-1B (RAB1B) in the cytoplasm, but the modulation of LINC00173 expression did not affect the expression of RAB1B at either the mRNA or protein levels. Instead, relying on the stimulation of RAB1B, LINC00173 could facilitate the extracellular secretion of proliferation-associated 2G4 (PA2G4) and stromal cell-derived factor 4 (SDF4; also known as 45-kDa calcium-binding protein) proteins, and knockdown of these proteins could reverse the NPC aggressive phenotype induced by LINC00173 overexpression. Moreover, in vivo LINC00173-knockdown models exhibited a marked slowdown in tumor growth and a significant reduction in lymph node and lung metastases. In summary, LINC00173 serves as a crucial driver for NPC progression, and the LINC00173-RAB1B-PA2G4/SDF4 axis might provide a potential therapeutic target for NPC patients.
Asunto(s)
Neoplasias Nasofaríngeas , ARN Largo no Codificante , Proteínas de Unión al ARN , Proteínas de Unión al GTP rab1 , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Unión al Calcio/genética , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Glicoproteínas/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Proteínas de Unión al GTP rab1/genética , Proteínas de Unión al GTP rab1/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteínas de Unión al ARN/metabolismoRESUMEN
Emerging evidence indicates that DNA methylation plays an important role in the initiation and progression of nasopharyngeal carcinoma (NPC). DNAJA4 is hypermethylated in NPC, while its role in regulating NPC progression remains unclear. Here, we revealed that the promoter of DNAJA4 was hypermethylated and its expression was downregulated in NPC tissues and cells. Overexpression of DNAJA4 significantly suppressed NPC cell migration, invasion, and EMT in vitro, and markedly inhibited the inguinal lymph node metastasis and lung metastatic colonization in vivo, while it did not affect NPC cell viability and proliferation capability. Mechanistically, DNAJA4 facilitated MYH9 protein degradation via the ubiquitin-proteasome pathway by recruiting PSMD2. Furthermore, the suppressive effects of DNAJA4 on NPC cell migration, invasion, and EMT were reversed by overexpression of MYH9 in NPC cells. Clinically, a low level of DNAJA4 indicated poor prognosis and an increased probability of distant metastasis in NPC patients. Collectively, DNAJA4 serves as a crucial driver for NPC invasion and metastasis, and the DNAJA4-PSMD2-MYH9 axis might contain potential targets for NPC treatments.
Asunto(s)
Transición Epitelial-Mesenquimal , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patología , Transición Epitelial-Mesenquimal/genética , Transducción de Señal , Movimiento Celular/genética , Neoplasias Nasofaríngeas/patología , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Invasividad Neoplásica/genética , Factor 2 Asociado a Receptor de TNF/metabolismo , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Proteínas del Choque Térmico HSP40/metabolismoRESUMEN
Although radiotherapy can promote antitumour immunity, the mechanisms underlying this phenomenon remain unclear. Here, we demonstrate that the expression of the E3 ubiquitin ligase, tumour cell-intrinsic tripartite motif-containing 21 (TRIM21) in tumours, is inversely associated with the response to radiation and CD8+ T cell-mediated antitumour immunity in nasopharyngeal carcinoma (NPC). Knockout of TRIM21 modulates the cGAS/STING cytosolic DNA sensing pathway, potentiates the antigen-presenting capacity of NPC cells, and activates cytotoxic T cell-mediated antitumour immunity in response to radiation. Mechanistically, TRIM21 promotes the degradation of the mitochondrial voltage-dependent anion-selective channel protein 2 (VDAC2) via K48-linked ubiquitination, which inhibits pore formation by VDAC2 oligomers for mitochondrial DNA (mtDNA) release, thereby inhibiting type-I interferon responses following radiation exposure. In patients with NPC, high TRIM21 expression was associated with poor prognosis and early tumour relapse after radiotherapy. Our findings reveal a critical role of TRIM21 in radiation-induced antitumour immunity, providing potential targets for improving the efficacy of radiotherapy in patients with NPC.
Asunto(s)
ADN Mitocondrial , Neoplasias Nasofaríngeas , Humanos , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/metabolismo , Recurrencia Local de Neoplasia , UbiquitinaciónRESUMEN
Chemoresistance is the leading cause of poor prognosis in head and neck squamous cell carcinoma (HNSC); however, promising biomarkers to identify patients for stratified chemotherapy are lacking. Sideroflexin 3 (SFXN3) is an important mitochondrial serine transporter during one-carbon metabolism, which is involved in the proliferation of cancer cells. However, the specific role of SFXN3 in HNSC remains unknown. In this study, we performed expression and survival analysis for SFXN3 in pan-cancer using data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) and found that SFXN3 served as a potential oncogene in HNSC. Notably, SFXN3 expression was found to be positively associated with enriched tumor-infiltrating macrophages, other immune suppressive cells, and immune checkpoint expression and resistance to paclitaxel. Gene, clinical, and immune variables included in the univariate and multivariate analyses showed that SFXN3 expression was an independent risk factor. Moreover, the LINC01270/hsa-miR-29c-3p/SFXN3 axis was identified as the most likely upstream non-coding RNA-related pathway of SFXN3 in HNSC using bioinformatic analysis, expression analysis, correlation analysis, and survival analysis. Taken together, our findings demonstrated that a non-coding RNA-mediated high expression of SFXN3 is a prognostic biomarker and is associated with the immunosuppressive microenvironment in HNSC.
Asunto(s)
Neoplasias de Cabeza y Cuello , MicroARNs , Carbono , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Humanos , Proteínas de la Membrana , MicroARNs/genética , Paclitaxel/uso terapéutico , Pronóstico , ARN no Traducido , Serina , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Microambiente Tumoral/genéticaRESUMEN
Epitranscriptomic remodeling such as N6 -methyladenosine (m6 A) modification plays a critical role in tumor development. However, little is known about the underlying mechanisms connecting m6 A modification and nasopharyngeal carcinoma (NPC) progression. Here, CBX1 is identified, a histone methylation regulator, to be significantly upregulated with m6 A hypomethylation in metastatic NPC tissues. The m6 A-modified CBX1 mRNA transcript is recognized and destabilized by the m6 A reader YTHDF3. Furthermore, it is revealed that CBX1 promotes NPC cell migration, invasion, and proliferation through transcriptional repression of MAP7 via H3K9me3-mediated heterochromatin formation. In addition to its oncogenic effect, CBX1 can facilitate immune evasion through IFN-γ-STAT1 signaling-mediated PD-L1 upregulation. Clinically, CBX1 serves as an independent predictor for unfavorable prognosis in NPC patients. The results reveal a crosstalk between epitranscriptomic and epigenetic regulation in NPC progression, and shed light on the functions of CBX1 in tumorigenesis and immunomodulation, which may provide an appealing therapeutic target in NPC.
Asunto(s)
Heterocromatina , Neoplasias Nasofaríngeas , Humanos , Línea Celular Tumoral , Proliferación Celular/genética , Epigénesis Genética/genética , Heterocromatina/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Factor de Transcripción STAT1/genéticaRESUMEN
Radiotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC), and approximately 20% of patients experience treatment failure due to tumour radioresistance. However, the exact regulatory mechanism remains poorly understood. Here, we show that the deubiquitinase USP44 is hypermethylated in NPC, which results in its downregulation. USP44 enhances the sensitivity of NPC cells to radiotherapy in vitro and in vivo. USP44 recruits and stabilizes the E3 ubiquitin ligase TRIM25 by removing its K48-linked polyubiquitin chains at Lys439, which further facilitates the degradation of Ku80 and inhibits its recruitment to DNA double-strand breaks (DSBs), thus enhancing DNA damage and inhibiting DNA repair via non-homologous end joining (NHEJ). Knockout of TRIM25 reverses the radiotherapy sensitization effect of USP44. Clinically, low expression of USP44 indicates a poor prognosis and facilitates tumour relapse in NPC patients. This study suggests the USP44-TRIM25-Ku80 axis provides potential therapeutic targets for NPC patients.
Asunto(s)
Carcinogénesis/genética , Roturas del ADN de Doble Cadena/efectos de la radiación , Reparación del ADN/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Ubiquitina Tiolesterasa/genética , Apoptosis/genética , Apoptosis/efectos de la radiación , Carcinogénesis/metabolismo , Línea Celular , Línea Celular Tumoral , Metilación de ADN , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de la radiación , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Autoantígeno Ku/genética , Autoantígeno Ku/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Regiones Promotoras Genéticas/genética , Tolerancia a Radiación/genética , Análisis de Supervivencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinaciónRESUMEN
Increasing evidence has revealed the roles of long noncoding RNAs (lncRNAs) as tumor biomarkers. Here, we introduce an immune-associated nine-lncRNA signature for predicting distant metastasis in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). The nine lncRNAs are identified through microarray profiling, followed by RT-qPCR validation and selection using a machine learning method in the training cohort (n = 177). This nine-lncRNA signature classifies patients into high and low risk groups, which have significantly different distant metastasis-free survival. Validations in the Guangzhou internal (n = 177) and Guilin external (n = 150) cohorts yield similar results, confirming that the signature is an independent risk factor for distant metastasis and outperforms anatomy-based metrics in identifying patients with high metastatic risk. Integrative analyses show that this nine-lncRNA signature correlates with immune activity and lymphocyte infiltration, which is validated by digital pathology. Our results suggest that the immune-associated nine-lncRNA signature can serve as a promising biomarker for metastasis prediction in LA-NPC.
Asunto(s)
Neoplasias Nasofaríngeas , ARN Largo no Codificante , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica/métodos , Humanos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/patología , ARN Largo no Codificante/genéticaRESUMEN
Importance: Microbiota-tumor interactions have qualified microbiota as a promising prognostic biomarker in various types of cancers. Although the nasopharynx acts as a crucial niche of the upper respiratory tract microbiome, whether the intratumoral microbiota exists and its clinical significance in nasopharyngeal carcinoma (NPC) remain uncertain. Objective: To evaluate the clinical significance of intratumoral microbiota for individual prognostication in patients with NPC. Design, Setting, and Participants: This retrospective cohort study included NPC biopsy samples from 2 hospitals: Sun Yat-sen University Cancer Center (Guangzhou, China) and Zhejiang Cancer Hospital (Hangzhou, China) between January 2004 and November 2016, with follow-up through November 2020. A total of 802 patients were included according to the following criteria: with histologically proven NPC, without distant metastasis at initial diagnosis, had not received antitumor treatment before biopsy sampling, aged between 18 and 70 years, with complete medical records and regular follow-up, without a history of cancer, and successfully extracted enough DNA for experiments. Main Outcomes and Measures: The primary end point was disease-free survival, and the secondary end points included distant metastasis-free survival and overall survival. To assess the existence and load of intratumoral microbiota in 96 patients with NPC with or without tumor relapse, 16S rRNA sequencing and quantitative polymerase chain reaction were used. The associations between intratumoral bacterial load and clinical outcome were evaluated in 241 fresh-frozen NPC samples (training cohort) and validated in paraffin-embedded NPC samples of internal (n = 233) and external (n = 232) validation cohorts. Metagenomic and transcriptome analyses were performed to ascertain the origin and underlying mechanism of intratumoral bacteria. Results: A total of 802 patients with NPC (mean [SD] age, 46.2 [10.6] years; 594 [74.1%] male) were enrolled. Microbiota presented within NPC tumor tissues, among which Corynebacterium and Staphylococcus predominated. Patients with a high bacterial load in the training cohort had inferior rates of disease-free survival (hazard ratio [HR], 2.90; 95% CI, 1.72-4.90; P < .001), distant metastasis-free survival (HR, 3.18; 95% CI, 1.58-6.39; P < .001), and overall survival (HR, 3.41; 95% CI, 1.90-6.11, P < .001) than those with a low bacterial load, a finding that was validated by the internal and external validation cohorts. Single-nucleotide variant analysis revealed that the nasopharyngeal microbiota was the main origin of NPC intratumoral bacteria. Transcriptome and digital pathology analyses demonstrated that a higher intratumoral bacterial load was negatively associated with T-lymphocyte infiltration. Conclusions and Relevance: Intratumoral bacterial load was a robust prognostic tool for patients with NPC in this cohort study, indicating potential guidance for treatment decisions in patients at different levels of risk of malignant progression.
Asunto(s)
Microbiota , Neoplasias Nasofaríngeas , Adolescente , Adulto , Anciano , Biomarcadores , China/epidemiología , Estudios de Cohortes , Femenino , Hospitales , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/patología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Nucleótidos , Pronóstico , ARN Ribosómico 16S , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVES: Dysphagia is common in patients with acute ischemic stroke patients (AIS) and it increases the risk of aspiration pneumonia after AIS. The volume-viscosity swallow test (V-VST) is a useful dysphagia screening tool. Therefore, we aim to explore the association between dysphagia (using the modified V-VST) and aspiration pneumonia in acute ischemic stroke patients. PATIENTS AND METHODS: All patients with acute ischemic stroke (AIS) admitted during 1 January 2018 and 31 December 2018 were screened in this study by completing the modified V-VST within 24 hours after admission. The information of aspiration pneumonia was obtained from electronic medical system (EMS) and discharge notes. RESULTS: Among 624 AIS patient, there were 152(24.36%) patients who suffered from aspiration pneumonia (95% CI, 20.65% - 27.35%) during hospitalization. Among all of them, patients with both impaired safety and impaired efficacy (HR, 7.53, 95%CI, 3.42-16.58, P < 0.001)) had a higher risk of aspiration pneumonia than those with only safety impaired (HR, 2.38, 95%CI, 1.40-4.04, P < 0.001) or only efficacy impaired (HR, 2.47, 95%CI, 1.33-4.57, P = 0.004). The risk of aspiration pneumonia was also associated with their completed volume at each viscosity. The patients with all impairment of three viscosities were also found to be related to the higher risk of developing aspiration pneumonia (P = 0.029). CONCLUSIONS: The Modified V-VST is an easy-hand on, reliable screening tool for dysphagia among patients with AIS. Patient subgroup analyses based on the modified V-VST might be able to predict the risk of aspiration pneumonia during hospitalization.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neumonía por Aspiración/complicaciones , Neumonía por Aspiración/tratamiento farmacológico , Accidente Cerebrovascular/complicaciones , Viscosidad/efectos de los fármacosRESUMEN
OBJECTIVE: Metabolic syndrome has been identified as a prognostic predictor in multiple cancers. This study aimed to evaluate the impact of metabolic syndrome on the clinical outcome of patients with nasopharyngeal carcinoma (NPC) and its mechanism. METHODS: A cohort of 2003 NPC patients with a median follow-up time of 96.3 months (range: 4.1-120.0 months) were enrolled in this analysis. Kaplan-Meier curves and the Log rank test were used to determine the differences in progression-free survival (PFS), cancer specific survival (CSS) and overall survival (OS). Univariate and multivariable analyses were used to identify independent prognostic predictors. Untargeted metabolomics (LC-HRMS) was used to detect the serum metabolic profiles of 10 well-matched patients with or without metabolic syndrome. Differential metabolite-based enrichment analysis and pathway analysis were performed to identify the potential mechanism of metabolic syndrome in NPC. RESULTS: A total of 171/2003 (8.5%) patients were diagnosed with metabolic syndrome, and these patients tended to be male (P < 0.001) and older (P = 0.003). Patients with metabolic syndrome had poorer PFS (P = 0.011), CSS (P = 0.003) and OS (P = 0.001) than those without metabolic syndrome. Univariate and multivariable analyses showed that metabolic syndrome was a statistically significant and independent predictor for PFS (HR: 1.34, 95% CI: 1.03-1.75, P = 0.032), CSS (HR: 1.53, 95% CI: 1.12-2.08, P = 0.008), and OS (HR: 1.50, 95% CI: 1.13-2.00, P = 0.006). The serum metabolic profile of patients with metabolic syndrome was distinct from that of patients without metabolic syndrome. A total of 319 differential metabolites [log2(FC)>1 or log2 (FC)<-1] were identified and were significantly involved in D-glutamine and D-glutamate metabolism, and valine, leucine and isoleucine biosynthesis. CONCLUSION: Metabolic syndrome can serve as a prognostic predictor and guide a more personalized therapy for NPC patients.
RESUMEN
PURPOSE: Serum cystatin C has been considered as a significant prognostic factor for various malignancies. This study aimed to evaluate the relationship between serum cystatin C level before antitumor treatment and the prognosis of nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). PATIENTS AND METHODS: A cohort of 2077 NPC patients were enrolled between April 2009 and September 2012. The Kaplan-Meier curves and log rank tests were used to determine the differences of overall survival (OS) and disease-free survival (DFS). Univariate and multivariate Cox regression analyses were used to determine independent prognostic factors. RESULTS: Overall, 362/2077 (17.4%) patients had high serum cystatin C level, and they were older and more male (both P<0.001), and they had higher TNM stage (all P<0.05). Kaplan-Meier analysis revealed that patients with high serum cystatin C had worse OS (P<0.001) and DFS (P<0.001). Univariate and multivariate Cox regression analysis showed that high serum cystatin C level was an independent prognostic predictor of OS (HR: 1.56, 95%CI: 1.25-1.95) and DFS (HR: 1.38, 95%CI: 1.13-1.68). Subgroup analysis based on TNM stage revealed that advanced-stage NPC patients with high serum cystatin C had poorer OS (P<0.001) and DFS (P<0.001). CONCLUSION: Our results revealed that high serum cystatin C level before antitumor treatment can predict clinical outcomes of NPC patients treated with IMRT, and it can guide clinicians to formulate more personalized therapy for NPC patients.