Background Lung adenocarcinoma (LUAD) patients experiencing lymph node metastasis (LNM) always exhibit poor clinical outcomes. A biomarker or gene signature that could predict survival in these patients would have a substantial clinical impact, allowing for earlier detection of mortality risk and for individualized therapy. Methods With the aim to identify a novel mRNA signature associated with overall survival, we analysed LUAD patients with LNM extracted from The Cancer Genome Atlas (TCGA). LASSO Cox regression was applied to build the prediction model. An external cohort was applied to validate the prediction model. Results We identified a 4-gene signature that could effectively stratify a high-risk subset of these patients, and time-dependent receiver operating characteristic (tROC) analysis indicated that the signature had a powerful predictive ability. Gene Set Enrichment Analysis (GSEA) showed that the high-risk subset was mainly associated with important cancer-related hallmarks. Moreover, a predictive nomogram was established based on the signature integrated with clinicopathological features. Lastly, the signature was validated by an external cohort from Gene Expression Omnibus (GEO). Conclusion In summary, we developed a robust mRNA signature as an independent factor to effectively classify LUAD patients with LNM into low- and high-risk groups, which might provide a basis for personalized treatments for these patients.

No abstract

HIF-α may play an important role in the process of tumorigenesis as well as tumor progression. Although a number of investigations have established the significance of HIF-1α in several human tumors, there is still little information available on the clinical significance of HIF-2α expression in non-small cell lung cancer (NSCLC). In present study, immunohistologic expression of HIF-1α/ HIF-2α was studied in a tissue microarray of 140 Stage I-III NSCLCs and correlated with clinicopathologic parameters and clinical outcome. We found that HIF-1α/ HIF-2α showed a cytoplasmic pattern of expression in tumor cells while normal lung components showed negative or weak cytoplasmic staining. High HIF-1α and HIF-2α expression was noted in 49/140 (35.0%) and in 64/140 (45.7%) of the cases respectively. There was no direct correlation between HIF-1α and HIF-2α expression ( p = 0.200). The high HIF-2α expression was associated with histology (squamous cell carcinoma vs. adenocarcinomas) in these patients ( p = 0.001). Patients in advanced tumor stage had frequent high expression of HIF-2α ( p = 0.007), and the similar high expression was also observed in advanced T or N stage ( p = 0.030 and 0.043, respectively). HIF-1α showed a marginal association with T stage ( p = 0.084), which showed a higher expression in early tumor stage. Univariate analysis of the overall survival demonstrates that HIF-2α expression but not HIF-1α was related to poor outcome ( p = 0.005) and it retained significance in multivariate analysis ( p = 0.046). In conclusion, HIF-2α expression was related to tumor size, lymph node metastasis, tumor stage and histology. We also found a positive prognostic value of HIF-2α protein expression. HIF-2α might serve as a potential prognosis biomarker in evaluating progression and prognosis of NSCLC. We believe that our study will be of great benefit to the clinical treatment and prognostic evaluation of NSCLC.

Insulin-like growth factor 2 messenger RNA-binding proteins have been described to associate with malignant process in many cancers. However, the role of insulin-like growth factor 2 messenger RNA-binding protein family has not been thoroughly elucidated in non-small cell lung cancer. This study was to investigate the expression profile, clinical significance, and biological function of insulin-like growth factor 2 messenger RNA-binding proteins family in non-small cell lung cancer. The expression levels of IGF2BP1-IGF2BP3 in tumor and adjacent normal tissues were determined, and association with clinicopathological features and overall survival was investigated by analyzing The Cancer Genome Atlas lung cancer database. Proliferation, migration, invasion assays, and flow-cytometry analysis were used to investigate the biological function in vitro. Insulin-like growth factor 2 messenger RNA-binding protein expression levels were significantly increased in non-small cell lung cancer compared to adjacent normal lung tissues. Chi-square test indicated that IGF2BP1 and IGF2BP3 expressions correlated with some meaningful clinical characteristics in non-small cell lung cancer. Kaplan-Meier analysis showed that high-level expression of IGF2BP1 or IGF2BP3 predicted poor overall survival in lung adenocarcinoma patients. Multivariate regression analysis showed that high level of IGF2BP3 was an independent risk factor for poor prognosis in lung adenocarcinoma patients (hazard ratio = 1.616, p = 0.017). In vitro, knockdown of IGF2BP3 inhibited lung adenocarcinoma cell proliferation by inducing cell cycle arrest and apoptosis, and undermined abilities of migration and invasion, and overexpression of IGF2BP3 could promote malignant phenotypes in lung adenocarcinoma cells. Our study revealed that expression of insulin-like growth factor 2 messenger RNA-binding proteins was widely upregulated and correlated with some certain clinicopathological features in non-small cell lung cancer. Especially, in insulin-like growth factor 2 messenger RNA-binding protein family, IGF2BP3 might play the most important role in tumor aggressiveness and prognosis in lung adenocarcinoma, and IGF2BP3 might serve as a potential therapeutic target and a novel prognostic biomarker in lung adenocarcinoma patients.

E2F activators (E2F1-3) codify a family of transcription factors (TFs) in higher eukaryotes. E2F activators are involved in the cell cycle regulation and synthesis of DNA in mammalian cells, and their overexpression has been detected in many human cancers. However, their clinical significance has not been deeply researched in non-small-cell lung cancer (NSCLC), and bioinformatics analysis has never been reported to explore their clinical role in NSCLC. In the current study, we investigated the expression and prognostic value of E2F activators in NSCLC patients through the "TCGA datasets" and the "Kaplan-Meier plotter" (KM plotter) database. Hazard ratio (HR), 95 % confidence intervals, and log-rank P were calculated. Compared with normal tissue samples, E2F activators were overexpressed in NSCLC tissues, in lung adenocarcinoma (LUAD) tissues, and in lung squamous cell carcinoma (LUSC) tissues. In NSCLC patients, E2F1 expression was significantly correlated with age, sex, and tumor stage. E2F2 expression was found to be significantly correlated with sex and tumor size. We further demonstrated that E2F1 and E2F2 overexpressions were significantly associated with poor prognosis. In LUAD patients, E2F1 expression was significantly correlated with tumor size and tumor stage. E2F2 expression was significantly correlated with lymph node status and tumor stage. E2F1 and E2F2 overexpression showed a significant association with poor prognosis, while E2F3 overexpression was significantly correlated to better prognosis. In LUSC patients, E2F1 was concluded to be significantly correlated with tumor stage. However, E2F activators were not found to be correlated to prognosis.

BackgroundCisplatin (DDP)-based systemic chemotherapy has been widely used in the treatment of postoperative or advanced NSCLC patients, however, its effective rate is only 14~40%. HIF-2α can upregulate drug-resistant-related genes expression and lead to chemotherapy resistance in many tumors. However, little is known about the relationship between HIF-2α and chemotherapy resistance of lung cancer cells.Material/MethodsIn our study, the siRNA expression vectors targeting the HIF-2α gene were designed, constructed, and transfected into A549 cells. MTT assay and western blot analysis of P-glycoprotein 1 (P-gp) were used to explore the transfer influence of HIF-2α gene silencing on the A549 cells in the cisplatin-based chemotherapy resistance.ResultsAfter transfection with the siRNAHIF-2α into A549 cells, mRNA and protein expression of HIF-2α were downregulated. At the same time, expression of P-gp decreased significantly. Furthermore, the sensitivity to cisplatin significantly increased.ConclusionsThe constructed siRNA expression vectors can effectively suppress the expression of HIF-2α and P-gp, which then can reverse the chemotherapy resistance of A549 cells.

Purpose: To clarify the correlation between KIF11 (kinesin family member 11) and clinicopathologic characteristics of non-small cell lung cancer (NSCLC) and identify the prognostic value of KIF11 in patients with NSCLC. Methods: For investigating the expression of KIF11 in NSCLC, two tissue microarrays (TMAs: one contained 60 paired NSCLC tissues and paratumor tissues, the other contained 140 NSCLC tissues and 10 normal lung tissues) were constructed, stained, and scored. The Cancer Genome Atlas (TCGA) datasets were used to explore the differential expression level of KIF11 between NSCLC and paratumor. Kaplan-Meier survival curves were plotted and multivariate analysis were carried out. Results: The staining of KIF11 mainly distributed throughout the cytoplasm of tumor cells. Its expression was higher in NSCLC than paratumor cells, and similar results were obtained from TCGA datasets. We found that high expression of KIF11 had a significant correlation with lymph node metastases ( p = 0.024) and pathologic stage ( p = 0.018); that significant difference was not found in any other clinicopathologic characteristic. As univariate and multivariate analysis showed, KIF11 expression was significantly correlated with overall survival time of NSCLC ( p = 0.002, p = 0.025, respectively). High KIF11 expression was found to significantly associate with overall survival of stage II–III ( p = 0.001) and lung adenocarcinoma ( p = 0.036). Conclusion: High KIF11 expression predicts poor outcome in NSCLC. KIF11 is expected to be a viable prognostic biomarker for NSCLC.

As a member of the tripartite motif family, tripartite motif-containing protein 59 (TRIM59) serves as an E3 ubiquitin ligase in various cellular processes, including intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy and carcinogenesis. The present study aimed to investigate the expression and prognostic value of TRIM59 in patients with non-small cell lung cancer (NSCLC). Expression of TRIM59 in patients with NSCLC was measured by immunohistochemistry in tissue microarrays. Datasets from The Cancer Genome Atlas (TCGA) were used to further verify the expression level of TRIM59 in NSCLC, lung adenocarcinoma and lung squamous cell carcinoma (LUSC). The prognostic value of TRIM59 in NSCLC was also analyzed. Immunohistochemistry revealed that TRIM59 was primarily located in the cytoplasm of tumor cells. Analysis of TCGA datasets revealed that TRIM59 was more highly expressed in tumor tissues than in normal tissues (P<0.0001). Furthermore, the TRIM59 expression level was associated with tumor differentiation (P=0.012), while no association was observed between TRIM59 expression and any other clinicopathological parameters. However, the average overall survival rate of patients with NSCLC in the high TRIM59 expression group was significantly lower than that in the low expression group (P=0.014), especially in patients with LUSC (P=0.016) and patients with poor differentiation (P=0.033). The multivariate analysis indicated that high TRIM59 expression is an independent prognostic factor in patients with NSCLC (P=0.018) and was associated with poor prognosis in patients with NSCLC. Therefore, TRIM59 may serve as a novel molecular biomarker to predict the prognosis of patients with NSCLC.