Identification and validation of a novel five-gene signature in high-risk MYCN-not-amplified neuroblastoma.

OBJECTIVE: High-risk neuroblastoma patients often have poor outcomes despite multi-treatment options. The risk stratification of high-risk MYCN-not-amplified (HR-MYCN-NA) patients remains difficult. This study aims to identify a gene set signature that can help further stratify HR-MYCN-NA patients for a potential personalized therapeutic strategy. METHODS: Three microarrays and one single-cell RNA sequence dataset were acquired and analyzed. Firstly, the prognostic-related genes (PRGs) in HR-MYCN-NA tumor cells were identified using TARGET-NB and GSE137804 datasets. Then, the prognostic model was established by LASSO-Cox regression, and verified in external cohort (GSE49710, GSE45547). Moreover, a time-dependent receiver operating characteristic curve (ROC) and area under the ROC (AUC) was used to assess survival prediction. A nomogram was established to predict the 1-, 3- and 5-year overall survival (OS) of HR-MYCN-NA patients. RESULTS: In the training set, a five-PRGs signature, which include GAL, GFRA3, MARCKS, PSMD13, and ZNHIT3 genes, was identified and successfully stratified HR-MYCN-NA patients into ultra-high risk (UHR) and high-risk (HR) subtypes (HR = 4.29, P < 0.001). ROC curve analysis confirmed its predictive power (AUC = 0.74-0.82), suggesting a good predictive efficacy. Consistently, high-risk scores also predicted worse OS (HR = 2, P = 0.033) in the external validation dataset (AUC = 0.67-0.71). Moreover, the overall C-index of the nomogram was 0.75 (P < 0.001), which indicated good agreement between the observed and predicted survival rates. Further integrating the five PRGs signature with clinical factors, these 5 gene signature (HR = 4.45, P < 0.001) and tumor grade (HR = 4.15, P = 0.02) were found to be independent prognostic factors for HR-MYCN-NA patients. CONCLUSION: The novel five PRGs signature could well predict the survival of HR-MYCN-NA patients, which may provide constructive information for these subsets.

Prognostic impact of tumor size on patients with neuroblastoma in a SEER-based study.

OBJECTIVE: The prognostic value of tumor size in neuroblastoma (NB) patients has not been fully evaluated. Our purpose is to elucidate the prognostic significance of tumor size in surgery performed on neuroblastoma patients. METHODS: Neuroblastoma patients diagnosed from 2004 to 2015 were selected from the Surveillance, Epidemiology, and End Results Program (SEER) for the study. Univariate and multivariate Cox proportional hazard regression models were used to identify risk factors and the independent prognostic influences of tumor size on NB patients. Overall survival (OS) was analyzed through univariate Cox regression analysis. To determine the optimal cutoff value of tumor size, we first divided the cohort into three groups (≤5 cm, 5-10 cm, >10 cm). Subsequently, the patients were divided into two groups repeatedly, with tumor size at 1 cm intervals. The cutoff value that maximized prognostic outcome difference was selected. Furthermore, we performed the Kaplan-Meier methods to visually present differences in prognosis between the optimal tumor size cutoff value in different subgroups. RESULTS: A total of 591 NB patients who met the inclusion criteria were selected from the SEER database in this study. Cox analysis showed that age >1 year (HR = 2.42, p < 0.0001), originate from adrenal site (HR = 1.7, p = 0.014), distant stage (HR = 6.4, p < 0.0001), undifferentiated grade (HR = 1.94, p = 0.002), and large tumor size (HR = 1.5, p < 0.0001) independently predicted poor prognosis. For tumor size, there were significant differences in tumor size distribution in different ages, tumor grade, disease stage, and primary site subgroup but not in sex, race, and histology subgroup. Furthermore, both univariate (HR = 4.96, 95% CI 2.31-10.63, p < 0.0001) and multivariable analysis (HR = 2.8, 95% CI 1.29-6.08, p < 0.0001) indicated the optimal cutoff value of tumor size was 4 cm for overall survival of NB patients. Using a 4 cm of tumor size cutoff in subgroups, we found that it can identify poor prognosis patients whatever their age or primary site. Interestingly, tumor size of 4 cm cutoff can only identify unfavorable NB patients with diagnosis at distant-stage disease, or differentiated grade tumor, but not with regional and local or undifferentiated tumor. CONCLUSIONS: Tumor size is first to be recognized as a key prognostic factor of neuroblastoma patients and a cutoff value >4 cm might predict poor prognosis, which should be included in the evaluation of prognostic factors for NB.

Systematic analysis using a bioinformatics strategy identifies SFTA1P and LINC00519 as potential prognostic biomarkers for lung squamous cell carcinoma.

Lung cancer has high incidence and mortality rates, in which lung squamous cell carcinoma (LUSC) is a primary type of non-small cell lung carcinoma (NSCLC). The aim of our study was to discover long non-coding RNAs (lncRNAs) associated with diagnose and prognosis for LUSC. RNA sequencing data obtained from LUSC samples were extracted from The Cancer Genome Atlas database (TCGA). Two prognosis-associated lncRNAs (including SFTA1P and LINC00519) were selected from LUSC samples, and the expression levels were also verified to be associated abnormal in LUSC clinical samples. Our findings demonstrate that lncRNAs SFTA1P and LINC00519 exert important functions in human LUSC and may serve as new targets for LUSC diagnosis and therapy.

Tumor suppressive microRNA-124a inhibits stemness and enhances gefitinib sensitivity of non-small cell lung cancer cells by targeting ubiquitin-specific protease 14.

Increasing evidence has shown that microRNAs (miRNAs) play a significant functional role by directly regulating respective targets in cancer stem cell (CSC)-induced non-small cell lung cancer (NSCLC) progression and resistance to therapy. In this study, we found that hsa-miR-124a was downregulated during spheroid formation of the NSCLC cell lines SPC-A1 and NCI-H1650 and NSCLC tissues compared with normal lung cells and tissues. Patients with lower hsa-miR-124a expression had shorter overall survival (OS) and progression free survival (PFS). Moreover, ubiquitin-specific protease 14 (USP14) was confirmed to be a direct target of hsa-miR-124a. Furthermore, concomitant low hsa-miR-124a expression and high USP14 expression were correlated with a shorter median OS and PFS in NSCLC patients. Cellular functional analysis verified that the tumor suppressor hsa-miR-124a negatively regulated cell growth and self-renewal, and promoted apoptosis and gefitinib sensitivity of lung cancer stem cells by suppressing its target gene USP14. Our results provide the first evidence that USP14 is a direct target of hsa-miR-124a, and that hsa-miR-124a inhibits stemness and enhances the gefitinib sensitivity of NSCLC cells by targeting USP14. Thus, hsa-miR-124a and USP14 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC.

Effect of hydrophobicity of core on the anticancer efficiency of micelles as drug delivery carriers.

Recently, micelles, which are self-assembled by amphiphilic copolymers, have attracted tremendous attention as promising drug delivery systems for cancer treatment. Thus, the hydrophobic core of the micelles, which could efficiently encapsulate small molecular drug, will play a significant role for the anticancer efficiency. Unfortunately, the effect of hydrophobicity of micellar core on its anticancer efficiency was rarely reported. Herein, the amphiphilic diblock polymers of poly(ethylene glycol) and polyphosphoester with different side groups (butyl, hexyl, octyl) were synthesized to tune the hydrophobicity of the micellar core. We found that the in vitro cytotoxicity of the DOX-loaded micelles decreased with the increasing hydrophobicity of micellar core due to the drug release rate. However, following systemic delivery, the DOX-loaded micelles with the most hydrophobic core exhibited the most significant inhibition of tumor growth in a MDA-MB-231 tumor model, indicating the importance of hydrophobicity of core on the antitumor efficacy of drug delivery systems.