Oncogenic and immunological roles of RACGAP1 in pan-cancer and its potential value in nasopharyngeal carcinoma.

A particular GTPase-activating protein called RACGAP1 is involved in apoptosis, proliferation, invasion, metastasis, and drug resistance in a variety of malignancies. Nevertheless, the role of RACGAP1 in pan-cancer was less studied, and its value of the expression and prognostic of nasopharyngeal carcinoma (NPC) has not been explored. Hence, the goal of this study was to investigate the oncogenic and immunological roles of RACGAP1 in various cancers and its potential value in NPC. We comprehensively analyzed RACGAP1 expression, prognostic value, function, methylation levels, relationship with immune cells, immune infiltration, and immunotherapy response in pan-cancer utilizing multiple databases. The results discovered that RACGAP1 expression was elevated in most cancers and suggested poor prognosis, which could be related to the involvement of RACGAP1 in various cancer-related pathways such as the cell cycle and correlated with RACGAP1 methylation levels, immune cell infiltration and reaction to immunotherapy, and chemoresistance. RACGAP1 could inhibit anti-tumor immunity and immunotherapy responses by fostering immune cell infiltration and cytotoxic T lymphocyte dysfunction. Significantly, we validated that RACGAP1 mRNA and protein were highly expressed in NPC. The Gene Expression Omnibus database revealed that elevated RACGAP1 expression was associated with shorter PFS in patients with NPC, and RACGAP1 potentially influenced cell cycle progression, DNA replication, metabolism, and immune-related pathways, resulting in the recurrence and metastasis of NPC. This study indicated that RACGAP1 could be a potential biomarker in pan-cancer and NPC.

m6A demethylase FTO renders radioresistance of nasopharyngeal carcinoma via promoting OTUB1-mediated anti-ferroptosis.

Radiotherapy is a valid treatment for nasopharyngeal carcinoma (NPC), and radioresistance is the main cause of local NPC treatment failure. However, the underlying mechanisms and valuable markers of radioresistance for NPC remain have not been established. In this study, we observed that the m6A mRNA demethylase fat mass and obesity-associated protein (FTO) was significantly upregulated in radioresistant NPC tissues and cells relative to parental radiosensitive NPC tissues and cells. FTO enhances radioresistance by repressing radiation-induced ferroptosis in NPC. Mechanistically, FTO acts as an m6A demethylase to erase the m6A modification of the OTUB1 transcript and promote the expression of OTUB1, thereby inhibiting the ferroptosis of cells induced by radiation and finally triggering the radiotherapy resistance of NPC. Furthermore, our in vivo experiment results showed that the FTO inhibitor, FB23-2, and the ferroptosis activator, erastin, altered tumor responsiveness to radiotherapy in NPC cell lines and patient-derived xenografts. Our findings reveal, for the first time, that FTO enhances NPC radiotherapy resistance by withstanding radiation-induced ferroptosis, suggesting that FTO may serve as a potential therapeutic target and valuable prognostic biomarker in patients with NPC.

Prognostic nomogram to predict the distant metastasis after intensity-modulated radiation therapy for patients with nasopharyngeal carcinoma.

ABSTRACT: Distant metastasis-free survival (DMFS) significantly differs among individuals with nasopharyngeal carcinoma (NPC). This analysis was carried out to find prognostic risk factors of DMFS and create a nomogram to predict DMFS for NPC patients who received Intensity-Modulated Radiation Therapy (IMRT).During March 2008 to January 2010, 437 patients with confirmed NPC from First Affiliated Hospital of Guangxi Medical University were recruited into this study. We developed a nomogram for predicting DMFS according to Cox regression analysis. Nomogram performance was assessed by concordance index (C-index), bootstrap validation method, and operating characteristics curves (ROC), respectively.Four independent prognostic factors for distant metastasis were identified, including age, chemotherapy, N-stage and residual tumor. C-index of the nomogram for prediction of DMFS was 0.807 (95% confidence interval, 0.726 to 0.738), which was confirmed using bootstrap validation, indicating satisfactory predictive accuracy. The calibration curves also showed adequate agreement in predicting the 3 and 5-year DMFS. The 3 and 5-year area under the curve (AUC) of ROC for nomogram and TMN stage were 0.828 and 0.612, 0.809, and 0.571, respectively. Classifying risk subgroups based on optimal cut-off value contributes to the effective discrimination of distant metastasis.The nomogram developed for this study is useful for oncologists to accurately predict DMFS and facilitates individualized treatment for patients with NPC.

Interactions between tumor mutation burden and immune infiltration in ovarian cancer.

The aim of the study was to evaluate the relationship between tumor mutational burden (TMB) and immune infiltration in ovarian cancer. We extracted somatic mutational data and gene expression profiles of ovarian cancer from The Cancer Genome Atlas (TCGA). The samples were separated into low and high TMB groups. Correlations between TMB and cancer prognosis were analyzed and immune cell infiltration in the high and low TMB subgroups was calculated using the CIBERSORT package software. High TMB was significantly related to an improved survival rate. We identified 4 TMB-related core genes that were significantly associated with prognosis. Furthermore, mutations in the 4 genes were associated with immune cell infiltration. We also found a high proportion of naive B cells and activated NK cells in the high TMB group, while increased proportions of memory B cells and plasma cells were found in the low TMB group. Overall, our study indicated that patients with a higher TMB level experienced a favorable survival outcome and this may influence immune infiltration in ovarian cancer. Furthermore, the 4 TMB-related core genes were highly correlated with prognosis and the level of immune cell infiltration.

Identification of novel biomarkers and small-molecule compounds for nasopharyngeal carcinoma with metastasis.

The purpose of this study was to investigate novel biomarkers and potential mechanisms in nasopharyngeal carcinoma (NPC) patients with metastasis.Two microarray datasets (GSE103611 and GSE36682) were obtained from GEO database, differentially expressed genes (DEGs) and differentially expressed miRNA (DEMs) were identified, Gene ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted with DEGs and DEMs targeted genes. Protein-protein interactions (PPI) network of the DEGs and DEMs targeted genes were constructed, furthermore, Connectivity Map (CMap) database was applied to select the potential drugs with therapeutic effects.Overall, we identified 396 upregulated and 19 downregulated DEGs. Additionally, we identified 1 upregulated DEM, miR-135b, and a downregulated DEM, miR-574-5p. Functional enrichment analysis indicated that both DEGs and DEMs targeted genes participated in biological process (BP) of regulation of transcription from RNA polymerase II promoter, DNA-templated positive regulation of transcription, and Epstein-Barr virus infection signaling pathway. Besides, upregulated EP300 gene was a hub node both in DEGs and DEMs target genes. CMap database analysis indicated that sanguinarine, verteporfin, and chrysin are potential drugs for prevention and treatment of NPC metastasis.In summary, the common hub gene, biological process and pathway identified in the study provided a novel insight into the potential mechanism of NPC metastasis. Furthermore, we identified several possible small molecule compounds for treatment of NPC metastasis.

A Nomogram for the Prognosis of Nasopharyngeal Carcinoma with MR Imaging-Detected Tumor Residue at the End of Intensity-Modulated Radiotherapy.

OBJECTIVE: This study set out to institute an effective nomogram to predict the prognosis of nasopharyngeal carcinoma (NPC) using magnetic resonance imaging (MRI)-detected residual tumor at the end of intensity-modulated radiotherapy (IMRT). BACKGROUND: This study retrospectively analyzed the prognostic factors of NPC using MRI-detected residual tumor at the end of IMRT, in order to individualize the treatment of patients with poor prognosis as early as possible. METHODS: Overall, 162 NPC patients with local or regional residual tumor at the end of IMRT were retrospectively analyzed. Based on multivariate Cox regression analysis using the backward stepwise method, a nomogram was generated to predict the prognosis of these patients. Identification, calibration, clinical applicability and reproducibility were evaluated by C-index, time-dependent AUC, calibration curve and bootstrap verification. According to the best cut-off value of total score of prognoses calculated by X-tile software, all patients were separated into either low-risk or high-risk group. RESULTS: The nomogram identified age, chemotherapy, N stage, lymph nodes necrosis are significant predictors of prognosis. The AUC of the prediction model is 0.754, and the consistency index is 0.724 (95% confidence interval is 0.659-0.788). The model has good discrimination ability. Through bootstrapping test, the consistency index, corrected slope was 0.723, 0.861, respectively. The calibration slope of predicting 3-year and 5-year overall survival was 1.006 and 1.071, respectively. The calibration curve showed satisfactory calibration effect and good net benefit. The best cut-off value of total score of prognoses calculated by X-tile software was 149.1. Kaplan-Meier survival curve showed that OS and DMFS in the high-risk group were substantially reduced compared to those in the low-risk group. CONCLUSION: We constructed and validated a new nomogram to help clinicians understand the prognosis of NPC patients with residue at the end of IMRT. With an estimate of the individual risk, clinicians can start treatment decisions as early as possible for high-risk patients with poor prognosis.

Network Pharmacology to Uncover the Molecular Mechanisms of Action of LeiGongTeng for the Treatment of Nasopharyngeal Carcinoma.

BACKGROUND Nasopharyngeal carcinoma (NPC) is a common head and neck cancer epidemic in southern China and southeast Asia. LeiGongTeng has been widely used for the treatment of cancers. The purpose of this study was to determine the pharmacological mechanism of action of LeiGongTeng in the treatment of NPC using a network pharmacological approach. MATERIAL AND METHODS The traditional Chinese medicine systems pharmacology (TCMSP) database was used to identify active ingredients and associated target proteins for LeiGongTeng. Cytoscape was utilized to create a drug-disease network and topology analysis was conducted to analyze the degree of each ingredient. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) online tool was applied for the construction and analysis of the protein-protein interaction (PPI) network, while Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) functional analyses were utilized to determine drug-disease common genes. RESULTS 22 active ingredients including kaempferol, nobiletin, and beta-sitosterol, and 30 drug-disease common genes including VEGFA, CASP3, ESR1, and RELA were identified. GO analysis indicated that 94 biological processes, including RNA polymerase II, apoptotic process, response to drug, cell adhesion, and response to hypoxia, were found to be associated with NPC. The KEGG enrichment analysis showed that 58 pathways, including the PI3K-Akt signaling pathway, microRNAs in cancer, tumor necrosis factor (TNF) signaling pathway and pathways in cancer were found to be associated with NPC. CONCLUSIONS LeiGongTeng exerts its therapeutic effect through various biological processes and signaling pathways since it acts on several target genes. Systematic pharmacology can be used to predict the underlying function of LeiGongTeng and its mechanism of action in NPC.

Comparison of intensity-modulated radiation therapy alone vs. intensity-modulated radiation therapy combined with chemotherapy in elderly nasopharyngeal carcinoma patients (aged >65 years).

PURPOSE: The efficacy and tolerability of adding chemotherapy to radiotherapy in the era of intensity-modulated radiation therapy (IMRT) remain controversial among older patients with nasopharyngeal carcinoma (NPC). The present study compared IMRT alone with IMRT in combination with chemotherapy in elderly NPC patients. METHODS: Between January 2011 and December 2014, 102 patients aged >65 years with NPC who received IMRT alone (IMRT group) or IMRT in combination with chemotherapy (IMRT/CT group) were enrolled. Patients from both treatment arms were pair-matched (1:1 ratio) based on six clinical factors. Differences in overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier method and Cox proportional hazards models, whereas the toxicity profile was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4. RESULTS: No significant differences were noted in OS (72.1% vs. 72.5%, p = 0.799), DFS (65.9% vs. 70.1%, p = 0.733), LRRFS (76.4% vs. 71.6%, p = 0.184), and DMFS (90.8% vs. 98.0%, p = 0.610) between the IMRT and IMRT/CT groups. Multivariate analyses showed that chemotherapy was not an independent factor for OS, DFS, LRRFS, and DMFS. However, the incidences of grade 3 vomiting/nausea (p = 0.000), leukopenia/neutropenia (p = 0.000), thrombocytopenia (p = 0.041), and anemia (p = 0.040) were significantly higher in the IMRT/CT group compared with the IMRT group. No grade 4 toxicities were observed. CONCLUSION: IMRT alone was similar to IMRT/CT in treating elderly NPC patients (age >65 years), with comparable survival outcomes and less grade 3 toxicities.

Gemcitabine plus cisplatin versus fluorouracil plus cisplatin as a first-line concurrent chemotherapy regimen in nasopharyngeal carcinoma: a prospective, multi-institution, randomized controlled phase II study.

BACKGROUND: The objective of this study was to evaluate the efficacy and safety of gemcitabine plus cisplatin concurrent chemoradiotherapy (CCRT) in patients with nasopharyngeal carcinoma. METHOD: Patients with NPC were randomly assigned to the gemcitabine plus cisplatin (GP) group or fluorouracil plus cisplatin (PF) group. Primary end-point was disease-free survival (DFS); secondary endpoints: overall survival, distant metastasis-free survival (DMFS), locoregional relapse-free survival, and treatment-related adverse events. RESULTS: Seventy-six patients were prospectively enrolled and the median follow-up time was 41 months (9-61 months). Three-year DFS were similar between the GP and PF groups (73.7% vs. 60.5%, HR 0.66, 95% CI 0.30-1.44; P = 0.30). Distant metastasis was the most common failure form in PF compared with GP (P = 0.034). Three-year DMFS was significantly better in the GP group than PF group (89.5% vs. 71.1%, P = 0.045). Grade 3-4 gastrointestinal toxicities (vomiting and diarrhea) were significantly more common in the PF group; grade 3-4 neutropenia and thrombocytopenia were more common in the GP group. CONCLUSION: Gemcitabine plus cisplatin could be used as an alternative regimen in CCRT for nasopharyngeal carcinoma.

Chemotherapy regimens containing taxanes or fluorouracil in nasopharyngeal carcinoma: Which better?

OBJECTIVES: The efficacy of various chemotherapy regimens in nasopharyngeal carcinoma (NPC) remains under debate. We compared the efficacy and toxicity of a taxane-based regimen and regimen including fluorouracil in NPC. MATERIALS AND METHODS: Eight-hundred and six patients with stage II-IVB NPC from four institutions in China were pair-matched (1:1 ratio) to the cisplatin plus fluorouracil (PF) group or cisplatin plus taxanes (TP) group using eight clinical factors. Overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier method and Cox regression model. Toxicities were assessed in all patients. RESULTS: Three-year DFS was significantly better in the TP group than PF group (82.5% vs. 72.7%, P=0.002), with no significant difference in OS, LRRFS or DMFS. TP led to significantly better DFS compared to PF in the subgroups advanced stage NPC, patients aged ≤45-years-old and female patients. In multivariate analysis, chemotherapy regimen was an independent prognostic factor for DFS [hazard ratio, 0.591, 95% CI 0.444-0.786, P=0.000]. Grade 3-4 leukopenia, neutropenia and anemia were significantly more common in the TP group; grade 3-4 mucositis, vomiting, vasculitis and diarrhea were more common in the PF group. CONCLUSION: Taxane-based regimens have a higher efficacy in NPC than regimens including fluorouracil, especially in patients with advanced stage, patients aged≤45-years-old and female patients.