Increased Angiogenin Expression Correlates With Radiation Resistance and Predicts Poor Survival for Patients With Nasopharyngeal Carcinoma
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ABSTRACT:
SUBMITTER: Guo S
PROVIDER: S-EPMC8427601 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The expression levels of CTLA-4 and CD28 were analyzed in 191 nasopharyngeal carcinoma (NPC) patients diagnosed and treated at our hospital between January 2010 and November 2011. The 3-year overall survival (OS) rate (91.4% vs. 81.2%,p = 0.043), failure-free survival (FFS) rate (82.8% vs. 68.0%, p = 0.009) and distant failure-free survival (D-FFS) rate (85.8% vs. 72.3%, p = 0.006) in the low tumor CTLA-4 expression group was higher than in the high tumor CTLA-4 group. There were no differences between the locoregional failure-free survival (LR-FFS) rates in the high and low tumor CTLA-4 expression groups. Moreover, no differences in the OS, FFS, D-FFS, or LR-FFS were observed between the groups with high and low lymphocyte CTLA-4 levels, high and low tumor CD28 levels, or high and low lymphocyte CD28 levels. Cox regression analysis confirmed the prognostic value of tumor CTLA-4 expression, particularly for D-FFS, in NPC patients (p = 0.044). NPC patients with high tumor CTLA-4 expression had a poorer prognosis than those with low expression.
| S-EPMC4914341 | biostudies-literature
Project description:Programmed death ligand-1 (PD-L1) is a potentially important tumor immunotherapy target. However, whether PD-L1 expression is associated with survival in nasopharyngeal carcinoma (NPC) remains controversial. The aim of the present study was to investigate the association between PD-L1 expression and prognosis in NPC. The expression of PD-L1 was assessed in tumor specimens from 120 patients with NPC using immunohistochemistry. Staining was evaluated using the H-score method. The associations between PD-L1 expression and clinical characteristics and prognosis were analyzed. Overall, 78% of the patients had stage I-III and 22% had stage IV disease. The estimated 5-year overall survival (OS) and disease-free survival (DFS) rates for the entire cohort were 87.5 and 70.1%, respectively. PD-L1 expression was detected in 85 (71%) patients and was localized to the tumor cells. High tumor expression of PD-L1 (median H-score ≥5) was associated with significantly poorer OS (P=0.023) and DFS (P=0.002). Univariate analysis indicated that low PD-L1 expression was associated with better DFS compared with high PD-L1 expression (HR=0.163, 95% CI: 0.044-0.600, P=0.006 for DFS). Multivariate analysis revealed that T stage (HR=8.190, 95% CI: 1.355-18.152; P=0.023) and PD-L1 expression level (HR=0.124, 95% CI: 0.031-0.509; P=0.001) served as independent prognostic factors for DFS. In conclusion, tumor PD-L1 expression was found to be a significant prognostic factor in NPC, and high PD-L1 expression may be of prognostic value for recurrence and metastasis following conventional treatments.
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Project description:Kelch proteins are implicated in the pathogenesis of many human diseases, including cancer. Nasopharyngeal carcinoma (NPC) is a rare malignancy in most countries, but prevalent in southern China and certain areas of Southeast Asia. In this study, we identified Kelch Domain Containing 4 (KLHDC4), an orphan member of the kelch repeat superfamily, as a prognosis marker for NPC. We examined the expression of KLHDC4 in 168 NPC cases by immunohistochemical staining and found a substantially higher level of KLHDC4 in NPC biopsies compared to adjacent normal nasopharyngeal mucosa. KLHDC4 expression was significantly related to the T classification (P <0.05), N classification (P <0.05) and total staging (P <0.01) in NPC, and patients with higher KLHDC4 expression had poorer overall (P <0.01) and metastasis-free survival (P <0.05) rates. Knockout (KO) of KLHDC4 via CRISPR/Cas9-mediated gene editing in NPC cell line dramatically inhibited cell proliferation, colony formation in soft agar and tumor formation in nude mice. In addition, cell migration and invasion were also impaired by KLHDC4 depletion as revealed by wound healing and Transwell assay. Mechanically, loss of KLHDC4 markedly induced spontaneous apoptosis in NPC cells, as evidenced by increased levels of cleaved caspase-3 and cleaved PARP. Consistently, KLHDC4 knockout cell-derived xenografts also showed elevated cleaved caspase-3 and PARP but reduced Ki-67 staining. In conclusion, our results suggest that KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis. Thus, KLHDC4 may serve as a prognosis biomarker and a potential therapeutic target for NPC.
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Project description:BACKGROUND AND PURPOSE:We evaluated the relationship between patient-, tumor-, and treatment-related features and radiation-induced lymphopenia (RIL) and evaluated the correlation between RIL and survival outcome in NPC patients to help improve the treatment strategy. METHODS:This retrospective study included 374 patients with stage II-IVa NPC who had been treated with definitive RT and were enrolled from 2004 to 2015; The associations between the G3-4 RIL (absolute lymphocyte count, ALC?<? 0.5?×?109 cells/L) during RT and patient-, tumor-, and treatment-related factors were assessed using Cox regression analyses. The correlation between ALC nadir and survival was examined using a Kaplan-Meier analysis, compared with the log-rank test, and confirmed by a Cox proportional hazards analysis. RESULTS:In the multivariate analysis, lower baseline ALC and intensity modulated radiation therapy (IMRT) (vs. 2 dimensional-conformal radiation therapy,2D-CRT) were identified as 2 independent factors that were associated with G3-4 RIL. In the multivariate survival analysis, patients with G3-4 ALC nadir had longer local recurrence-free survival durations (LRFS) (vs. G0-2 nadir, HR?=?0.548, P?=?0.005) and longer progression-free survival durations (PFS) (vs. G0-2 nadir, HR?=?0.676, P?=?0.022), while patients with G4 ALC nadir had a shorter distant-metastasis-free survival duration (DMFS) (vs. G0-2 nadir, hazard ratio [HR]?=?2.567, P?=?0.037). CONCLUSIONS:In the study, lymphopenia during RT were affected by baseline ALC and RT modality independently. Moreover, G3-4 ALC nadir was independently linked with longer PFS and LRFS durations, while G4 ALC nadir was independently linked with a shorter DMFS duration.
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Project description:Wnt signaling pathways and autophagy play an essential role in tumor progression. Canonical Wnt signaling pathways in radiation resistance have been studied in the past, but it remains unclear whether the noncanonical Wnt signaling pathways can affect tumor radiation resistance through protective autophagy. Nasopharyngeal carcinoma, a particular subtype of head and neck squamous cell carcinoma, relies on radiation therapy. In this study, we found that radioactive rays could significantly promote the expression of Wnt noncanonical signaling pathways ligands in nasopharyngeal carcinoma, among which Wnt5A was the most markedly altered. We have demonstrated that Wnt5a can reduce the radiation sensitivity of nasopharyngeal carcinoma in vitro and in vitro experiments. Meanwhile, we found much more greater autophagosomes in overexpressed-Wnt5A nasopharyngeal carcinoma cells by electron microscopy. Further mechanism exploration revealed that Beclin1 is the main target of Wnt5A, and knocking down Beclin1 can partially reduce Wnt5a-induced radiation resistance. By studying Wnt5A-mediated protective autophagy in promoting radiation resistance in nasopharyngeal carcinoma cells, we hope that the Wnt5A and Beclin1 can become effective targets for overcoming radiation resistance in the future.
| S-EPMC9066197 | biostudies-literature
Project description:Glioblastoma (GBM) is a highly aggressive brain tumour, where patients respond poorly to radiotherapy and exhibit dismal survival outcomes. The mechanisms of radioresistance are not completely understood. However, cancer cells with an immature stem-like phenotype are hypothesised to play a role in radioresistance. Since the progenitor marker neuron-glial-2 (NG2) has been shown to regulate several aspects of GBM progression in experimental systems, we hypothesised that its expression would influence the survival of GBM patients. Quantification of NG2 expression in 74 GBM biopsies from newly diagnosed and untreated patients revealed that 50% express high NG2 levels on tumour cells and associated vessels, being associated with significantly shorter survival. This effect was independent of age at diagnosis, treatment received and hypermethylation of the O(6)-methylguanine methyltransferase (MGMT) DNA repair gene promoter. NG2 was frequently co-expressed with nestin and vimentin but rarely with CD133 and the NG2 positive tumour cells harboured genetic aberrations typical for GBM. 2D proteomics of 11 randomly selected biopsies revealed upregulation of an antioxidant, peroxiredoxin-1 (PRDX-1), in the shortest surviving patients. Expression of PRDX-1 was associated with significantly reduced products of oxidative stress. Furthermore, NG2 expressing GBM cells showed resistance to ionising radiation (IR), rapidly recognised DNA damage and effectuated cell cycle checkpoint signalling. PRDX-1 knockdown transiently slowed tumour growth rates and sensitised them to IR in vivo. Our data establish NG2 as an important prognostic factor for GBM patient survival, by mediating resistance to radiotherapy through induction of ROS scavenging enzymes and preferential DNA damage signalling.
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Project description:BACKGROUND: LATS2, which encodes a novel serine/threonine kinase, is known to be important in centrosome duplication and in the maintenance of genomic stability. Recently, a potential role for LATS2 in cancer has been reported. In breast cancer and acute lymphoblastic leukemia (ALL), LATS2 mRNA is downregulated and has been suggested to be a tumor suppressor. However, the role of LATS2 in nasopharyngeal carcinoma has not been investigated. In this study, we aimed to investigate the expression pattern of LATS2 and its clinicopathological involvement in nasopharyngeal carcinoma to understand its effect on cell survival. METHODS: Using quantitative real time PCR and immunoblotting, the expression of LATS2 was detected in nasopharyngeal carcinoma cell lines and in the immortalized nasopharyngeal epithelial cell line NP69. Using immunohistochemistry, we analyzed LATS2 protein expression in 220 nasopharyngeal carcinoma cases. The association of LATS2 protein expression with the clinicopathological characteristics and the prognosis of nasopharyngeal carcinoma were subsequently assessed. Using methylation specific PCR, we detected the methylation status of the LATS2 promoter. RNA interference was performed by transfecting siRNA to specifically knock down LATS2 expression in 5-8F and CNE2. RESULTS: LATS2 protein was detected in 178 of 220 (80.91%) cases of nasopharyngeal carcinoma. LATS2 overexpression was a significant, independent prognosis predictor (P = 0.037) in nasopharyngeal carcinoma patients. Methylation specific PCR revealed that 36.7% (11/30) of nasopharyngeal carcinoma tissues and all of the chronic nasopharyngeal inflammation samples were methylated. Functional studies showed that the suppression of LATS2 expression in nasopharyngeal carcinoma (5-8F and CNE2) cell lines by using specific small interfering (siRNA) resulted in the inhibition of growth, induction of apoptosis and S-phase cell cycle increase. Overexpression of LATS2 in NP69 stimulated cell proliferation. CONCLUSIONS: Our results indicate that LATS2 might play a role in the tumorigenesis of nasopharyngeal carcinoma by promoting the growth of nasopharyngeal carcinoma cells. Transfection with specific siRNA might be feasible for the inhibition of growth, induction of apoptosis and S phase increase in nasopharyngeal carcinoma.
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Project description:Interferon-stimulated gene 15 (ISG15), the first identified ubiquitin-like protein, is known for its anti-viral capacity. However, its role in tumorigenesis remains controversial. Here, using RNA-seq profiling analysis, we identified ISG15 as a differentially expressed gene in nasopharyngeal carcinoma (NPC) and validated its overexpression in NPC samples and cells. High ISG15 levels in NPC tissues were correlated with more frequent local recurrence and shorter overall survival and disease-free survival. ISG15 overexpression promoted a cancer stem cell phenotype in NPC cells, including increased colony and tumorsphere formation abilities, pluripotency-associated genes expression, and in vivo tumorigenicity. By contrast, knockdown of ISG15 attenuated stemness characteristics in NPC cells. Furthermore, overexpression of ISG15 increased NPC cell resistance to radiation and cisplatin (DDP) treatment. Our study demonstrates a protumor role of ISG15, and suggests that ISG15 is a prognostic predictor and a potential therapeutic target for NPC.
| S-EPMC4941359 | biostudies-literature
Project description:Objective:Menage a trois 1 (MAT1) is a targeting subunit of cyclin-dependent kinase-activating kinase and general transcription factor IIH kinase, which modulates cell cycle, transcription and DNA repair. Its dysregulation is responsible for diseases including cancers. To further explore the role of MAT1 in breast cancer, we investigated the pathways in which MAT1 might be involved, the association between MAT1 and molecular subtypes, and the role of MAT1 in clinical outcomes of breast cancer patients. Methods:We conducted immunohistochemistry staining on tissue microarray and immunofluorescence staining on sections of MAT1 stable breast cancer cells. Also, we performed Kyoto Encyclopedia of Genes and Genomes pathway analysis, correlation analysis and prognosis analysis on public databases. Results:MAT1 was involved in multiple pathways including normal physiology signaling and disease-related signaling. Furthermore, MAT1 positively correlated with the protein status of estrogen receptor and progesterone receptor, and was enriched in luminal-type and human epidermal growth factor receptor 2-enriched breast cancer in comparison with basal-like subtype at both mRNA and protein levels. Correlation analysis revealed significant association between MAT1 mRNA amount and epithelial markers, mesenchymal markers, cancer stem cell markers, apoptosis markers, transcription markers and oncogenes. Consistently, the results of immunofluorescence stain indicated that MAT1 overexpression enhanced the protein abundance of epidermal growth factor receptor, vimentin, sex determining region Y-box 2 and sine oculis homeobox homolog 1. Importantly, Kaplan-Meier Plotter analysis reflected that MAT1 could serve as a prognostic biomarker predicting worse relapse-free survival and metastasis-free survival. Conclusions:MAT1 is correlated with molecular subtypes and is associated with unfavorable prognosis for breast cancer patients.
| S-EPMC6037588 | biostudies-literature
Project description:BackgroundPrevious studies have shown that RNA Polymerase III Subunit G (POLR3G) has oncogenic effects in cultured cells and mice. However, the role of POLR3G in transitional cell carcinoma (TCC) has not been reported. This study explores the potential of POLR3G as a novel molecular marker for TCC.MethodsThe RNA sequencing data and clinical information of patients with TCC were downloaded from The Cancer Genome Atlas official website. Transcriptome analysis was performed as implemented in the edgeR package to explore whether POLR3G was up-regulated in TCC tissues compared to normal bladder tissues. The expression of POLR3G in bladder cancer cell line T24 and human uroepithelial cell line SV-HUC-1 were detected via quantitative real time polymerase chain reaction (qRT-PCR). Correlations between POLR3G expression and clinicopathological characteristics were analyzed using Mann-Whitney U test or Kruskal-Wallis H test. Clinicopathological characteristics associated with overall survival were explored using the Kaplan-Meier method and Cox regression analyses. Gene set enrichment analysis (GSEA) was performed to explore the associated gene sets enriched in different POLR3G expression phenotypes and the online tool Tumor IMmune Estimation Resource (TIMER) was used to explore the correlation between POLR3G expression and tumor immune infiltration in TCC.ResultsTranscriptome analysis showed that POLR3G was significantly up-regulated in TCC tissues compared to normal bladder tissues. Furthermore, qRT-PCR revealed high expression of POLR3G in T24 cells compared to SV-HUC-1 cells. Overall, POLR3G expression was associated with race, tumor status, tumor subtype, T classification, and pathological stage. Kaplan-Meier survival analysis revealed that higher POLR3G expression was associated with lower overall survival. The univariate Cox regression model revealed that age at diagnosis, pathological stage, and POLR3G expression were associated with prognosis of TCC patients. Further multivariate analyses identified these three clinicopathological characteristics as independent prognostic factors for overall survival. GSEA analysis showed that several gene sets associated with tumor development and metastasis, including TGF-β signaling, PI3K-AKT-mTOR signaling, and IL6-JAK-STAT3 signaling, were significantly enriched in POLR3G high expression phenotype. Immune infiltration analysis revealed that the expression of POLR3G was significantly correlated with infiltrating levels of immune cells, including CD8+ T cells, neutrophils, and dendritic cells; and the expression of POLR3G was also significantly correlated with the expression of immune checkpoint molecules, such as PD1, PD-L1, PD-L2, CTLA4, LAG3, HAVCR2, and TIGIT.ConclusionsPOLR3G was up-regulated in TCC and high POLR3G expression correlated with poor prognosis. POLR3G can potentially be used as a prognostic marker for TCC and might be of great value in predicting the response to immunotherapy.
| S-EPMC7646299 | biostudies-literature