IL-17A promotes the proliferation of human nasopharyngeal carcinoma cells through p300-mediated Akt1 acetylation.

Interleukin (IL)-17A is a T helper (Th)17 cell-secreted cytokine that is able to induce various inflammatory responses. There is emerging evidence that IL-17A is generated in the cancer microenvironment of human nasopharyngeal carcinoma (NPC). However, the role of IL-17A in NPC remains unclear. Thus, the present study aimed to examine the direct influence of IL-17A stimulation on the proliferation of human NPC cells and identify the underlying molecular mechanisms. Furthermore, E1A binding protein p300 (p300)-mediated AKT serine/threonine kinase 1 (Akt1) acetylation and its role in regulating the proliferation of NPC cells was investigated. The results of the current study demonstrated that IL-17A stimulation in vitro increased the proliferation of human NPC cells. Furthermore, Akt1 acetylation was identified to be enhanced in human NPC cells induced by IL-17A. Additionally, p300 induction was demonstrated to be required for Akt1 acetylation in human NPC cells following exposure to IL-17A. Functionally, p300-mediated Akt1 acetylation contributed to the proliferation of human NPC cells stimulated by IL-17A. In conclusion, the results of the present demonstrate a novel activity of IL-17A that promotes human NPC cell proliferation via p300-mediated Akt1 acetylation. This may provide a potential strategy for the treatment of patients with NPC through the inhibition of IL-17A or its receptors.

A 80-gene set potentially predicts the relapse in laryngeal carcinoma optimized by support vector machine.

OBJECTIVE: The present study was performed to identify a gene set for predicting the relapse in laryngeal carcinoma using large data analysis methods. METHODS: Two gene expression profile data of laryngeal carcinoma (GSE27020 and GSE25727) were downloaded from public database. Genes associated with tumor relapse, namely informative genes, were identified by Cox regression analysis. Then the protein-protein interaction (PPI) network consisting of informative genes was constructed. Afterwards, the optimized support vector machine (SVM) classifier was constructed to classify the relapsed laryngeal carcinoma samples based on genes in specific PPI network. Furthermore, the efficiency of the SVM classifier was verified by other two independent datasets. RESULTS: A total of 331 informative genes were obtained from GSE27020 and GSE25757 datasets. A PPI network specific to laryngeal carcinoma relapse was constructed which contained informative genes and critical non-informative genes. The top 10 genes in specific PPI network were APP, NTRK1, TP53, PTEN, FN1, ELAVL1, HSP90AA1, XPO1, LDHA and CDK2 ranked by BC (betweenness centrality) value. The optimized SVM classifier including top 80 genes showed accuracy of 100% to classify the relapsed cases from laryngeal carcinoma samples. Next, the efficiency of the SVM classifier to predict relapse samples was verified in another independent datasets, which showed accuracy of 97.47%. The informative genes in the optimized SVM classifier were enriched in several pathways associated with tumor progression. CONCLUSION: A 80-gene set was identified as biomarker to predict the relapse of laryngeal carcinoma, which would be potentially applied in decision of different treatments for patients with different relapse risks.

C5a promotes the proliferation of human nasopharyngeal carcinoma cells through PCAF-mediated STAT3 acetylation.

The anaphylatoxin C5a is a chemoattractant that can induce various inflammatory responses in vivo via the C5a receptor (C5aR). There is emerging evidence that C5a is generated in the cancer microenvironment. However, the role of C5a in human nasopharyngeal carcinoma (NPC) remains largely unclear. Thus, the present study aimed to examine the direct influence of C5a stimulation on the proliferation of human NPC cells and to identify the underlying molecular mechanisms. The effects of C5a stimulation on the proliferation of human NPC cells were studied in vitro, and P300/CBP-associated factor (PCAF)­mediated signal transducer and activator of transcription 3 (STAT3) acetylation and its role in regulating the proliferation of NPC cells was subsequently explored. Our results demonstrated that C5a stimulation increased the proliferation of human NPC cells in vitro. STAT3 acetylation was further found to be enhanced in human NPC cells induced by C5a. Moreover, PCAF induction was required for STAT3 acetylation in human NPC cells by exposure to C5a. Functionally, PCAF-mediated STAT3 acetylation contributed to the proliferation of human NPC cells stimulated by C5a. These results illustrate the novel activity of the C5a-C5aR axis that promotes human NPC cell proliferation through PCAF­mediated STAT3 acetylation. This may provide a potential strategy for treating human NPC through inhibition of C5a or its receptors.

Association between the P53 codon 72 polymorphism and nasopharyngeal cancer risk.

The P53 codon 72 polymorphism has been identified as a critical biomarker in modifying the risk of nasopharyngeal cancer (NPC). Many studies have investigated the association between the polymorphism of P53 codon 72 and NPC risk; however, the findings across the published studies are inconsistent and inconclusive. To acquire a more precise assessment for this association, we conducted an updated meta-analysis. The PubMed, Embase, Web of Science, and Wanfang databases were searched for relevant case-control studies. Totally, seven independent publications with 1,133 cases and 1,678 controls were retrieved. The pooled odds ratio (OR) with corresponding 95% confidence interval (95% CI) was calculated. Increased risk of NPC was observed among individuals carrying the variant allele and genotypes of P53 codon 72 (OR Pro vs. Arg = 1.32, 95% CI 1.18-1.47, P OR < 0.001; OR ProPro vs. ArgArg = 1.90, 95% CI 1.51-2.39, P OR < 0.001; OR ProArg + ProPro vs. ArgArg = 1.33, 95% CI 1.13-1.57, P OR = 0.001; OR ProPro vs. ArgArg + ProArg = 1.65, 95% CI 1.35-2.01, P OR < 0.001). Stratified analyses by ethnicity and source of controls also identified this significant relationship in Asians, Caucasians, and hospital-based case-control studies. There was no publication bias risk in our study. The updated meta-analysis supports the evidence that the polymorphism of P53 codon 72 is a risk factor for the development of NPC among the populations of both Asian and Caucasian.

Let-7a inhibits proliferation and induces apoptosis by targeting EZH2 in nasopharyngeal carcinoma cells.

Let-7a is frequently downregulated in various types of human cancer including nasopharyngeal carcinoma. However, the underlying mechanism of let-7a action in nasopharyngeal carcinoma remains elusive. In this study, we show that the enhancer of zeste homolog 2 (EZH2) is a direct target of let-7a in human nasopharyngeal carcinoma cells. The inhibition of EZH2 in vitro by let-7a, EZH2 siRNA, attenuated nasopharyngeal carcinoma cell growth, inhibited cell proliferation and induced cell apoptosis. In addition, for each biological process we identified ontology-associated transcripts that significantly correlate with EZH2 expression. Finally, the expression of EZH2 significantly abrogated let-7a-mediated cell proliferation and apoptosis in the nasopharyngeal carcinoma cells. Taken together, our results suggest that let-7a and EZH2 may be potential therapeutic targets for nasopharyngeal carcinoma.

MiR-106b promotes cell proliferation via targeting RB in laryngeal carcinoma.

MiR-106b is frequently up-regulated in various types of human cancer including laryngeal carcinoma. However the underlying mechanism of miR-106b involved in laryngeal carcinoma remains elusive. Here we showed that reduction of miR-106b induced cell cycle G0/G1 arrest by targeting tumor suppressor RB in human laryngeal carcinoma cells. Further, Introducing RB cDNA without 3'UTR abrogated miR-106b-induced cell proliferation. Finally, there was an inverse relationship between RB and miR-106b expression in laryngeal carcinoma tissues. To our knowledge, these data indicate for the first time that miR-106b directly regulate cell cycle by targeting RB in laryngeal carcinoma and that miR-106b could be potential therapeutic approaches for laryngeal carcinoma.

Hsa-miR-34c suppresses growth and invasion of human laryngeal carcinoma cells via targeting c-Met.

MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively modulate gene expression at the post-transcriptional level. A growing number of studies has shown that more and more miRNAs are aberrantly expressed and involved in the pathogenesis of several types of cancers. Here, we report that the down-regulated hsa-miR-34c was also involved in oncogenesis of laryngeal carcinoma. Our studies indicated that hsa-miR-34c functioned as a tumor suppressor which inhibited growth and invasion of human laryngeal carcinoma cells. Furthermore, in our study, an inverse relationship between the expression of hsa-miR-34c and c-Met was identified in 10 paired fresh samples from tumor tissues and adjacent normal tissues. Infection of hsa-miR-34c mediated by lentivirus suppressed the expression of c-Met directly. In addition, introduction of c-Met cDNA lacking 3'-UTR largely abrogated hsa-miR-34c-induced cell growth and invasion inhibition. These findings suggest aberrantly down-regulated hsa-miR-34c is a critical factor that contributes to malignancy in human laryngeal carcinoma by a mechanism involving targeting of c-Met.

Activated mammalian target of rapamycin is associated with T regulatory cell insufficiency in nasal polyps.

BACKGROUND: Decreased infiltration of Foxp3+ T regulatory cell (Treg) is considered to be critical for the Th1/Th2 dysregulation of nasal polyps, while the cellular mechanism underlying Foxp3+ Treg insufficiency is currently not well defined. METHODS: We attempted to investigate the tissue expression of phosphorylated mammalian target of rapamycin (pmTOR) and infiltration of Foxp3+ Tregs in 28 nasal polyps and 16 controls by histological staining. We also evaluated the effects of blocking the mTOR signaling pathway with rapamycin on T cell phenotype selection and Foxp3+CD4+ Tregs expansion in a tissue culture system. RESULTS: Significantly increased infiltration of pmTOR+ inflammatory cells and decreased infiltration of Foxp3+CD4+ Tregs into nasal polyps was observed, with an inverse association. In the tissue culture system, we detected significantly elevated Foxp3 expression and IL-10 production, as well as an increased percentage of Foxp3+ Tregs in nasal polyps after blocking the mTOR signaling pathway with rapamycin. CONCLUSION: Here we demonstrate for the first time that the mTOR signaling pathway is associated with Foxp3+ Tregs insufficiency in nasal polyps. Inhibition of the mTOR signaling pathway may be helpful for enhancement of Foxp3+ Treg expansion, as well as modulation of T cell phenotype imbalances in nasal polyps.