Metastasis In Nasopharyngeal Carcinoma Patients Research Articles

275 A nomogram based on PET/CT signatures to predict early metastasis in nasopharyngeal carcinoma patients

275 A nomogram based on PET/CT signatures to predict early metastasis in nasopharyngeal carcinoma patients

Multi-omics fusion with soft labeling for enhanced prediction of distant metastasis in nasopharyngeal carcinoma patients after radiotherapy

Omics fusion has emerged as a crucial preprocessing approach in medical image processing, significantly assisting several studies. One of the challenges encountered in integrating omics data is the unpredictability arising from disparities in data sources and medical imaging equipment. Due to these differences, the distribution of omics futures exhibits spatial heterogeneity, diminishing their capacity to enhance subsequent tasks. To overcome this challenge and facilitate the integration of their joint application to specific medical objectives, this study aims to develop a fusion methodology for nasopharyngeal carcinoma (NPC) distant metastasis prediction to mitigate the disparities inherent in omics data. The multi-kernel late-fusion method can reduce the impact of these differences by mapping the features using the most suiTable single-kernel function and then combining them in a high-dimensional space that can effectively represent the data. The proposed approach in this study employs a distinctive framework incorporating a label-softening technique alongside a multi-kernel-based Radial basis function (RBF) neural network to address these limitations. An efficient representation of the data may be achieved by utilizing the multi-kernel to map the inherent features and then merging them in a space with many dimensions. However, the inflexibility of label fitting poses a constraint on using multi-kernel late-fusion methods in complex NPC datasets, hence affecting the efficacy of general classifiers in dealing with high-dimensional characteristics. The label softening increases the disparity between the two cohorts, providing a more flexible structure for allocating labels. The proposed model is evaluated on multi-omics datasets, and the results demonstrate its strength and effectiveness in predicting distant metastasis of NPC patients.

DNAJA4 suppresses epithelial-mesenchymal transition and metastasis in nasopharyngeal carcinoma via PSMD2-mediated MYH9 degradation

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.

Deep Learning for Predicting Distant Metastasis in Patients with Nasopharyngeal Carcinoma Based on Pre-Radiotherapy Magnetic Resonance Imaging.

Accurate pre-treatment prediction of distant metastasis in patients with Nasopharyngeal Carcinoma (NPC) enables the implementation of appropriate treatment strategies for high-risk individuals. To develop and assess a Convolutional Neural Network (CNN) model using pre-therapy Magnetic Resonance (MR) imaging to predict distant metastasis in NPC patients. We retrospectively reviewed data of 441 pathologically diagnosed NPC patients who underwent complete radiotherapy and chemotherapy at Renmin Hospital of Wuhan University (Hubei, China) between February 2012 and March 2018. Using Adobe Photoshop, an experienced radiologist segmented MR images with rectangular regions of interest. To develop an accurate model according to the primary tumour, Cervical Metastatic Lymph Node (CMLN), the largest area of invasion of the primary tumour, and image segmentation methods, we constructed intratumoural and intra-peritumoural datasets that were used for training and test of the transfer learning models. Each model's precision was assessed according to its receiver operating characteristic curve and accuracy. Generated high-risk-related Grad-Cams demonstrated how the model captured the image features and further verified its reliability. Among the four models, all intra-peritumoural datasets performed better than the corresponding intratumoural datasets, with the CMLN intra-peritumoural dataset exhibiting the best performance (average area under the curves (AUCs) = 0.88). There was no significant difference between average AUCs of the Max and NPC tumour datasets. AUCs of the eight datasets for the four models were higher than those of the Tumour-Node-Metastasis staging system (AUC=0.67). In most datasets, the xception model had higher AUCs than other models. The efficientnet-b0 and xception models efficiently extracted high-risk features. The CNN model predicted distant metastasis in NPC patients with high accuracy. Compared to the primary tumour, the CMLN better predicted distant metastasis. In addition to intratumoural data, peritumoural information can facilitate the prediction of distant metastasis. With a larger sample size, datasets of the largest areas of tumour invasion may achieve meaningful accuracy. Among the models, xception had the best overall performance.

Influence of widely targeted quantitative lipidomics on plasma lipid predictors and pathway dysregulation for nasopharyngeal carcinoma.

6030 Background: Dysregulation of lipid metabolism is closely associated with cancer progression. We aimed to establish a prognostic model to predict distant metastasis-free survival (DMFS) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC), based on widely targeted quantitative lipidomics. Methods: We measured and quantified the plasma lipid profiles of 179 patients with NPC using widely targeted quantitative lipidomics. Then, patients were randomly split into the training (125 patients, 69.8%) and validation (54 patients, 30.2%) sets. To identify distant metastasis-associated lipids, univariate Cox regression was applied to the training set ( p< 0.05). We employed a deep survival method called DeepSurv to develop our proposed model based on significant lipid species ( p< 0.01) and clinical biomarkers to predict DMFS. Concordance index and receiver operating curve analyses were performed to assess model effectiveness. We also explored the potential role of lipid alterations in the prognosis of NPC. Results: A total of 665 plasma endogenous lipid species consisting of 27 lipid classes and subclasses from 179 patients with NPC were annotated in lipidomics analysis. Forty lipids were recognized as distant metastasis-associated ( p< 0.05) by univariate Cox regression. The concordance indices of our proposed model were 0.764 (95% confidence interval (CI), 0.682–0.846) and 0.760 (95% CI, 0.649–0.871) in the training and validation sets, respectively. We also calculated the C-index values of the baseline survival model based only on clinical biomarkers, with 0.718 (95% CI, 0.591–0.845) and 0.672 (95% CI, 0.511–0.833) being detected in the training and validation sets, respectively, indicating the outstanding predictive performance of lipid biomarkers. High-risk patients had poorer 5-year DMFS compared with low-risk patients (Hazard ratio, 26.18; 95% CI, 3.52–194.80; p< 0.0001). Moreover, the six lipids were significantly correlated with immunity- and inflammation-associated biomarkers and were mainly enriched in metabolic pathways. Conclusions: Widely targeted quantitative lipidomics reveals plasma lipid predictors and pathway dysregulation for locoregionally advanced NPC, the prognostic model based on that demonstrated superior performance in predicting metastasis in NPC patients.

Adiponectin Suppresses Metastasis of Nasopharyngeal Carcinoma through Blocking the Activation of NF-κB and STAT3 Signaling.

Adiponectin is an adipocytokine with anti-inflammatory and anticancer properties. Our previous study has shown that blood adiponectin levels were inversely correlated to the risk of nasopharyngeal carcinoma (NPC), and that adiponectin could directly suppress the proliferation of NPC cells. However, the effect of adiponectin on NPC metastasis remains unknown. Here, we revealed in clinical studies that serum adiponectin level was inversely correlated with tumor stage, recurrence, and metastasis in NPC patients, and that low serum adiponectin level also correlates with poor metastasis-free survival. Coculture with recombinant adiponectin suppressed the migration and invasion of NPC cells as well as epithelial-mesenchymal transition (EMT). In addition, recombinant adiponectin dampened the activation of NF-κB and STAT3 signaling pathways induced by adipocyte-derived proinflammatory factors such as leptin, IL-6, and TNF-α. Pharmacological activation of adiponectin receptor through its specific agonist, AdipoRon, largely stalled the metastasis of NPC cells. Taken together, these findings demonstrated that adiponectin could not only regulate metabolism and inhibit cancer growth, but also suppress the metastasis of NPC. Pharmacological activation of adiponectin receptor may be a promising therapeutic strategy to stall NPC metastasis and extend patients' survival.

Using ultrasound radiomics analysis to diagnose cervical lymph node metastasis in patients with nasopharyngeal carcinoma.

This study aimed to explore the clinical value of ultrasound radiomics analysis in the diagnosis of cervical lymph node metastasis (CLNM) in patients with nasopharyngeal carcinoma (NPC). A total of 205 cases of NPC CLNM and 284 cases of benign lymphadenopathy with pathologic diagnosis were retrospectively included. Grayscale ultrasound (US) images of the largest section of every lymph node underwent feature extraction. Feature selection was done by maximum relevance minimum redundancy (mRMR) algorithm and multivariate logistic least absolute shrinkage and selection operator (LASSO) regression. Logistic regression models were developed based on clinical features, radiomics features, and the combination of those features. The AUCs of models were analyzed by DeLong's test. In the clinical model, lymph nodes in the upper neck, larger long axis, and unclear hilus were significant factors for CLNM (p < 0.001). MRMR and LASSO regression selected 7 significant features for the radiomics model from the 386 radiomics features extracted. In the validation dataset, the AUC value was 0.838 (0.776-0.901) in the clinical model, 0.810 (0.739-0.881) in the radiomics model, and 0.880 (0.826-0.933) in the combined model. There was not a significant difference between the AUCs of clinical models and radiomics models in both datasets. DeLong's test revealed a significantly larger AUC in the combined model than in the clinical model in both training (p = 0.049) and validation datasets (p = 0.027). Ultrasound radiomics analysis has potential value in screening meaningful ultrasound features and improving the diagnostic efficiency of ultrasound in CLNM of patients with NPC. • Radiomics analysis of gray-scale ultrasound images can be used to develop an effective radiomics model for the diagnosis of cervical lymph node metastasis in nasopharyngeal carcinoma patients. • Radiomics model combined with general ultrasound features performed better than the clinical model in differentiating cervical lymph node metastases from benign lymphadenopathy.

Juvenile Stroke in a Patient with Severe Large Vessel Atherosclerosis of the Neck Decades after Radiotherapy for Nasopharyngeal Carcinoma: Are Iatrogenic Endocrinopathies Additional Risk Factors?

Juvenile Nasopharyngeal carcinoma (NPC) is a rare head and neck cancer in Western Countries. Neck radiotherapy (RT) is a routine procedure for treating or preventing the nodal metastasis in NPC patients. Ionizing radiation from RT has been associated with enhanced atherosclerotic process of large vessel arteries of the neck and brain which results in higher incidence of cerebrovascular events.

TBL1X and Flot2 form a positive feedback loop to promote metastasis in nasopharyngeal carcinoma.

Metastasis is the main cause of death in patients with nasopharyngeal carcinoma (NPC). The molecular mechanisms underlying the metastasis of NPC remain to be elucidated. TBL1X has been shown abnormally expressed in diverse cancers. However, the role and mechanism of TBL1X in NPC remain unknown. Here, we showed TBL1X expression was significantly higher in metastatic NPC tissues compared to non-metastatic tissues and significantly correlated with TNM stage and metastasis of NPC patients. In addition, NPC patients with high TBL1X expression had a poor prognosis. TBL1X interacted with TCF4 to trans-activate Flot2 expression. TBL1X promoted NPC cell migration and invasion in vitro and in vivo through Flot2. Moreover, Flot2 increased the expression of TBL1X by upregulating c-myc, which was identified to be a positively regulatory transcription factor of TBL1X. TBL1X could restore the functional changes of NPC cells resulting from Flot2 alteration. TBL1X and Flot2 were positively correlated in NPC. Patients with high expression of both TBL1X and Flot2 possessed poorer overall survival (OS) and disease-free survival (DFS) compared to patients with high expression of any single one of the two proteins. Our findings demonstrate that TBL1X and Flot2 positively regulate each other to promote NPC metastasis, which provides novel potential molecular targets for NPC treatment.

A Nomogram Based on Circulating CD4+ T Lymphocytes and Lactate Dehydrogenase to Predict Distant Metastasis in Patients with Nasopharyngeal Carcinoma.

PurposeDistant metastasis is the main pattern of treatment failure in nasopharyngeal carcinoma (NPC) in the era of intensity-modulated radiotherapy (IMRT). We aimed to establish and validate a prognostic nomogram to identify patients with a high risk of distant metastasis.Patients and MethodsA total of 503 patients with nonmetastatic NPC were included in this retrospective study. We established a prognostic nomogram for distant metastasis-free survival (DMFS) based on the Cox proportional hazards model. The predictive discriminative ability and accuracy of the nomogram were assessed with the concordance index (C-index), receiver operating characteristic (ROC) curve, and calibration curve. The nomogram’s clinical utility was also evaluated using decision curve analysis (DCA) and Kaplan–Meier method. The predictive ability of the nomogram was validated in an independent cohort.ResultsThe multivariate analysis showed that circulating CD4+ T lymphocytes, lactate dehydrogenase (LDH), serum ferritin (SF), and N stage were independent prognostic factors for DMFS. Then, we constructed the nomogram based on these factors. The C-indexes of the nomogram for distant metastasis were 0.763 (95% CI: 0.685–0.841) and 0.760 (95% CI: 0.643–0.877) in the training cohort and validation cohort, respectively, which was higher than the 8th TNM staging system (0.672 and 0.677). The calibration curve showed that the prediction results of the nomogram were in high agreement with the actual observation. The ROC curve indicated that the nomogram had a better predictive ability than TNM staging. The DCA also demonstrated that the nomogram was clinically beneficial. In addition, the patients were classified into two different risk groups (high-risk, low-risk) by the nomogram.ConclusionAs a supplement to TNM staging, our nomogram could provide a more effective and accurate prognostic prediction of distant metastasis in NPC patients. It has the potential to guide the individualized treatment of patients to improve their survival.

Re-evaluation of the prognostic significance of retropharyngeal node metastasis in nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy.

To investigate the prognostic value of retropharyngeal lymphadenopathy in nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy. Retrospective studies were performed in a total of 1197 patients. We evaluated the incidence of the retropharyngeal node (RPN) metastasis and the characteristics of the metastatic RPN including laterality, size, necrosis, and extranodal neoplastic spread. RPN metastasis occured in 86.3% of patients. The RPN and level II metastasis shared similar survival outcomes. RPN metastasis was an independent prognostic factor for distant failure (hazard ratio =1.615; 95%confidence interval, 1.063-2.452; P=0.025), in which the laterality of RPN metastasis significantly influences both the distant failure (P=0.006) and disease progression (P=0.001). In N1 disease, the occurrence of unilateral and bilateral RPN metastasis resulted in significantly different outcomes of the disease-specific survival (P=0.045) and progression-free survival (P=0.049). The co-occurrence of bilateral RPN and cervical lymph nodes (CLN) metastasis was an independent adverse prognostic factor (P<0.01) for distant failure and disease progression but not for locoregional recurrence. Both the RPN and level II are the first stations of NPC lymph node metastasis. For N1-stage NPC patients, RPN metastasis, especially co-occurrence of bilateral RPN and CLN metastasis, have an adverse influence on survival outcomes.

Establishment and validation of a prognostic nomogram to predict early metastasis in nasopharyngeal carcinoma patients within six months after radiotherapy and to guide intensive treatment

PurposeThis study aimed to establish an effective prognostic nomogram to predict the risk of early metastasis (EM) in nasopharyngeal carcinoma (NPC) patients, as a guide for intensive treatment. Materials and methodsA total of 9021 patients with biopsy-confirmed NPC at our institute were enrolled in this study between December 2006 to December 2016. We randomized these patients using a proportion of 2/3 and 1/3 and selected 6044 and 2977 patients as the training and validation cohorts, respectively. All patients received radiotherapy with or without chemotherapy. Univariate and multivariate logistical regressions were used to identify independent risk factors. The nomogram’s predictive value was evaluated by concordance indexes (C-indexes), calibration curves, probability density functions (PDFs), and clinical utility curves (CUCs). ROC analysis using Delong test was used to compare efficiency between the nomogram and other risk factors. ResultsIn total, 174 (2.9%) and 81 (2.7%) patients in training and validation cohorts, respectively, had EM.Pretreatment plasma EBV DNA, N stage, LDH, ALP, BMI, and sex were independent predictive factors of EM. The C-indexes of nomogram were 0.756 (95% CI = 0.719–0.793) and 0.766 (95% CI = 0.720–0.813), in the training and validation cohorts, respectively. The C-index of the nomogram was significantly superior to any one of independent factors. According to the PDFs and CUCs and considering the balance of the true positive EM patients and true positive non-EM patients, we chose 5.0% as a threshold probability for clinical decision-making, which could distinguish about 85% and 48% of non-EM and EM patients, respectively. ConclusionOur nomogram had good accuracy in predicting EM incidence, and a 5.0% threshold was appropriate for clinical decision-making.

Analysis of Prognostic Risk Factors in Patients with Nasopharyngeal Carcinoma Treated with Radiotherapy by Magnetic Resonance Imaging

The purpose of the study was to explore the application value of magnetic resonance imaging (MRI) technology in the study of the prognosis of patients with nasopharyngeal carcinoma (NPC) after radiotherapy, and to analyze the risk factors leading to imaging residues, so as to provide reference for the treatment and prognosis of patients with NPC. The clinical data of 691 patients with NPC hospitalized from June 2008 to June 2016 were retrospectively analyzed. According to the results of magnetic resonance medical imaging, the residual data of patients with NPC after treatment were analyzed. Combined with t-stage and n-stage parameters, the image residual was divided into t-stage residual and n-stage residual. The radiological residues, residual regression time, survival time, recurrence and metastasis time were recorded. The radiological residual rate of NPC after radiotherapy was calculated, and the differences among groups were compared by chi-square test. The risk factors of image residual and residual regression time were analyzed by logistic regression model. The 5-year overall survival rate (OS), 5-year recurrence-free survival rate (LRFS), and 5-year distant metastasis-free survival rate (DMF) were calculated. Kaplan.Meier method was used to analyze the influence of various factors on the prognosis of patients, and logarithmic rank test was used to compare the difference of survival rate between the two groups. The results showed that the residual rate of T and N was 32.9% and 31.0% at the end of radiotherapy for NPC. In summary, magnetic resonance medical imaging technology can effectively evaluate the prognostic risk factors of patients with NPC after radiotherapy. Male, elderly, radioactivity residue, and high stage are the risk factors affecting the prognosis of patients with NPC after radiotherapy. The recurrence and metastasis of NPC patients can be effectively controlled by means of emphasizing radiotherapy combined with adjuvant chemotherapy.

Prognostic value of immune score in nasopharyngeal carcinoma using digital pathology

BackgroundTumor-infiltrating lymphocytes have been reported as prognostic markers in tumors. We aimed to assess the prognostic value of total T cell (CD3+) density, cytotoxic T cell (CD8+) density and memory...

Circulating miR-214-3p predicts nasopharyngeal carcinoma recurrence or metastasis

BackgroundDue to the remarkably stable form in the bloodstream, circulating microRNAs (miRNAs) are indicated as promising novel minimally invasive biomarkers in many cancers. However, available data of miRNAs in nasopharyngeal carcinoma (NPC) are relatively limited. MethodsBased on the GEO database and previous published reports, 21 dysregulated miRNAs were selected for screening via microarray analysis (20 NPC samples vs 10 controls). Dysregulated miRNAs were then detected and verified by the method of quantitative reverse transcription–polymerase chain reaction (qRT-PCR) in the training and validation sets. The candidate miR-214-3p was then evaluated in the evaluation set, including the association between miR-214-3p and clinicopathological characteristics, dynamic changes in NPC patients and the predictive value for NPC recurrence or metastasis. ResultsSeven miRNAs were significantly altered in comparison with healthy controls by microarray analysis. MiR-214-3p was the most significantly expressed in training and validation sets by qRT-PCR. Plasma miR-214-3p expressions were significantly associated with UICC stages and NPC recurrence or metastasis. Plasma miR-214-3p expressions showed a gradual decrease during the follow-up after treatment in NPC patients. Patients with recurrence or metastasis were always accompanied with higher levels of plasma miR-214-3p at the same time point. High pretreatment miR-214-3p expression (≥3.12) was significantly associated with NPC recurrence or metastasis by log-rank test using Kaplan-Meier survival curve analysis (P = 0.006). ConclusionsCirculating miR-214-3p can serve as a noninvasive biomarker for the prediction of recurrence or metastasis in NPC patients.

Emodin Inhibits EBV Reactivation and Represses NPC Tumorigenesis.

Nasopharyngeal carcinoma (NPC) is a unique malignancy derived from the epithelium of the nasopharynx. Despite great advances in the development of radiotherapy and chemotherapy, relapse and metastasis in NPC patients remain major causes of mortality. Evidence accumulated over recent years indicates that Epstein-Barr virus (EBV) lytic replication plays an important role in the pathogenesis of NPC and inhibition of EBV reactivation is now being considered as a goal for the therapy of EBV-associated cancers. With this in mind, a panel of dietary compounds was screened and emodin was found to have potential anti-EBV activity. Through Western blotting, immunofluorescence, and flow cytometric analysis, we show that emodin inhibits the expression of EBV lytic proteins and blocks virion production in EBV- positive epithelial cell lines. In investigating the underlying mechanism, reporter assays indicated that emodin represses Zta promoter (Zp) and Rta promoter (Rp) activities, triggered by various inducers. Mapping of the Zp construct reveals that the SP1 binding region is important for emodin-triggered repression and emodin is shown to be able to inhibit SP1 expression, suggesting that it likely inhibits EBV reactivation by suppression of SP1 expression. Moreover, we also show that emodin inhibits the tumorigenic properties induced by repeated EBV reactivation, including micronucleus formation, cell proliferation, migration, and matrigel invasiveness. Emodin administration also represses the tumor growth in mice which is induced by EBV activation. Taken together, our results provide a potential chemopreventive agent in restricting EBV reactivation and NPC recurrence.

Contribution of Nitric oxide synthase 3 genetic variants to nasopharyngeal carcinoma risk and progression in a Tunisian population.

We conduct this study to evaluate the clinical and functional impact of Nitric Oxide Synthase 3 (NOS3) T-786C and G894T genetic variants on nasopharyngeal carcinoma (NPC) risk and progression in a Tunisian population. 259 NPC patients and 169 healthy controls were enrolled into our case-control study. Blood samples were genotyped by the RFLP-PCR analysis. The levels of Nitric oxide (NO) were measured by a colorimetric assay kit in the plasma of NPC patients, healthy controls and according to NOS3 genotypes. The correlation between the NOS3 variants and the clinicopathological parameters was examined. We found no linkage disequilibrium between NOS3 T-786C and G894T variants. These results showed that NOS3 variants were genetically independent. In contrast to NOS3 T-786C, a significant association was found between NOS3 G894T polymorphism and NPC risk. The 894T allele decreased significantly in NPC patients and appeared as protective factor (OR = 0.65, CI 95%= 0.48-0.88, p = 0.006). NPC patients had significantly higher levels of plasma NO as compared to healthy controls (p = 0.0011). The T-786C mutation reduced the levels of plasma NO and decreased risk of lymph node metastasis in NPC patients (OR = 0.64, 95% CI = 0.43-0.96; p = 0.03). In contrast, NOS3 G894T polymorphism had no effects neither on NO plasma levels nor clinical parameters. This is the first study to associate NPC with significantly higher levels of plasma NO. NOS3-derived NO could play key roles in NPC pathogenesis. NOS3 variants differently contribute to NPC risk and progression in a Tunisian population. NOS3 G894T was associated with NPC risk. NOS3 T-786C decreased the levels of plasma NO and reduced the development of regional lymph node metastasis.

PNUTS mediates ionizing radiation-induced CNE-2 nasopharyngeal carcinoma cell migration, invasion, and epithelial-mesenchymal transition via the PI3K/AKT signaling pathway.

PurposeIonizing radiation (IR) is widely used for treating nasopharyngeal carcinoma (NPC). However, recent studies indicate that IR can also promote the migration and invasion of malignant tumors. Phosphatase 1 nuclear-targeting subunit (PNUTS), a novel interacting protein, was recently demonstrated to be involved in tumorigenesis and metastasis formation. This protein was hypothesized to take part in IR-induced migration and invasion in NPC cells in this study.Materials and methodsWestern blotting was used to detect how PNUTS was expressed in NPC cells with or without IR treatment. Wound-healing and Transwell assays were used to measure cell migration and invasion. Quantitative real-time PCR and Western blotting were used to determine the expression levels of PNUTS and epithelial–mesenchymal transition (EMT) proteins, respectively, after CNE-2 cells were infected with an adenovirus vector, ad-PNUTS, or transfected with PNUTS-specific siRNA. Finally, the expression levels of PI3K/AKT signaling-related proteins were detected by Western blotting.ResultsIR significantly promoted PNUTS expression and the migration and invasion in CNE-2 cells. Moreover, after exposure to IR, expression of the mesenchymal markers N-cadherin and vimentin increased, while that of the epithelial marker E-cadherin decreased. Silencing PNUTS remarkably attenuated IR-induced increases in cell migration and invasion and reversed the EMT process. Additionally, the overexpression of PNUTS restored the mobility and invasiveness of CNE-2 cells, which regained EMT characteristics. Furthermore, we found that PNUTS regulated IR-induced EMT via the PI3K/AKT signaling pathway.ConclusionOur research illustrates a relationship between PNUTS and IR-induced cell migration and invasion and provides a novel therapeutic target for preventing radiotherapy-induced metastasis in NPC patients.

Development and Validation of an MRI-Based Signature to Predict Distant Metastasis in Nasopharyngeal Carcinoma Before Initial Treatment: A Retrospective Cohort Study

Background: We aimed to identify an MRI-based model to assess the risk of individual distant metastasis in nasopharyngeal carcinoma (NPC) patients before initial treatment. Methods: In this retrospective cohort analysis, 176 patients with nasopharyngeal carcinoma were included. By using the PyRadiomics platform, we extracted imaging textures of primary tumors in all NPC patients who did not exhibit distant metastasis before treatment. We then used mRMR and LASSO algorithms to select the strongest features and build a logistic model to predict distant metastasis in these patients. We tested the independent statistical significance of multiple clinical variables by using a multivariate logistic regression analysis. Findings: In total, 2780 radiomic features were extracted from the NPC patients. A distant metastasis MRI-based signature (DMMS), comprising seven features, was constructed to classify NPC patients into high- and low-risk groups in the training cohort, and validated in the independent validation cohort. Patients with high-risk scores had shorter overall survival than patients with low-risk scores in the training cohort (P < 0·001). A radiomics nomogram, which was based on radiomic features and clinical variables, was developed to assess the risk of distant metastasis in each patient; it showed a significant predictive ability in the training cohort [AUC, 0·84; 95% confidence interval (CI), 0·75-0·90] and the validation cohort [AUC 0·79; 95% CI, 0·63-0·95)]. Interpretation: The DMMS is a visual prognostic tool for predicting distant metastasis in NPC patients. It has the potential to improve treatment decision-support by distinguishing patients at high or low risk of distant metastasis. Funding: This research received financial support from the National Natural Science Foundation of China (81571664, 81871323, 81801665, 81771924, 81501616, 81671851, and 81527805); the National Natural Science Foundation of Guangdong Province (2018B030311024); the Science and Technology Planning Project of Guangdong Province (2016A020216020); the Scientific Research General Project of Guangzhou Science Technology and Innovation Commission (201707010328); the China Postdoctoral Science Foundation (2016M600145), National Key R&D Program of China (2017YFA0205200, 2017YFC1308700, and 2017YFC1309100). Declaration of Interest: There are no conflicts of interest to declare. Ethical Approval: The study design was approved by the appropriate ethics review board, which waived the requirement for informed consent due to the retrospective nature of the study.

Increased Expression of Cullin 3 in Nasopharyngeal Carcinoma and Knockdown Inhibits Proliferation and Invasion.

This study aimed to investigate the clinical significance of cullin 3 expression in nasopharyngeal carcinoma (NPC), as well as to explore the regulatory mechanism of cullin 3 underlying the growth and metastasis of NPC cells. Our findings showed that the expression levels of cullin 3 were significantly increased in both NPC tissues and cell lines. A strong positive correlation was found between cullin 3 expression and the Ki-67-based proliferation index in NPC tissues. Moreover, cullin 3 overexpression was correlated with local relapse and distant metastasis in NPC patients. In vitro experiments showed that knockdown of cullin 3 caused a significant reduction in the proliferation of NPC cells, probably by inducing cell cycle arrest. In addition, downregulation of cullin 3 inhibited colony formation and the migratory and invasive capacities of NPC cells. The expression levels of PCNA and epithelial-to-mesenchymal transition (EMT)-related proteins were also meditated by cullin 3 in NPC cells. Based on these findings, we demonstrated that cullin 3 plays a promoting role in the malignant progression of NPC and suggest that the cullin 3-based ubiquitin proteasome pathway may be used as a promising therapeutic target for NPC.