Prognosis Of Non-small Cell Lung Cancer Patients Research Articles

Down-regulated microRNA-375 expression as a predictive biomarker in non-small cell lung cancer brain metastasis and its prognostic significance

Brain metastases (BM) are common among patients with non-small cell lung cancer (NSCLC) and have been associated with significant morbidity and limited survival. Early and sensitive detection of BM is essential for improving prognosis. Recently, microRNA-375(miR-375) which is specifically expressed in the brain has been found significantly dysregulated in many human cancers. However, there is still no data whether miR-375 is associated with higher risk of BM development in NSCLC. In this study, we detected the miR-375 expression using quantitative real-time PCR (qRT-PCR) and assessed its predictive and prognostic significance. Our result showed that miR-375 expression was significantly down-regulated in NSCLC patients with BM(BM+, N=30) compared with NSCLC without BM(BM-, N=30) (P<0.001). Statistical analysis indicated that low miR-375 expression was linked to advanced disease stage (P<0.001) and brain metastasis (P<0.001) in NSCLC patient. Survival analysis suggested that low-expression group had significantly shorter overall survival than high-expression group in NSCLC patients with BM(log-rank test: P<0.05) as well as the total cases(log-rank test: P<0.01). Multivariate Cox proportional hazards model analysis indicated that low miR-375 expression was independently linked to poor survival of patients with NSCLC (HR=5.48, 95% CI: 1.93–15.56, P=0.001). In addition, we found that VEGF and MMP-9 were over-expressed in down-regulated miR-375 expression cases. Collectively, this study demonstrated that miR-375 may play an important role as a predictive biomarker in brain metastasis and an independent prognostic factor in NSCLC. Over-expression of VEGF and MMP-9 may be the reason for poor prognosis of NSCLC patients with low miR-375 expression.

The expression of programmed death receptor 1 in non-small cell lung cancer and its clinicopathological features and prognosis showed a connection with epidermal growth factor receptor gene mutations

Objective: To investigate the relationships between the expression of programmed death 1 (PD-1) and the epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer (NSCLC). The study also attempted to investigate the clinicopathological features and prognosis in NSCLC patients. Methods: The expression of PD-1 protein in 88 cases of NSCLC tumor tissues and adjacent tissues was detected by immunohistochemistry. The mutations of EGFR in NSCLC were detected by Polymerase Chain Reaction-Amplification Refractory Mutation System(PCR-ARMS) method. The expression of PD-1 and patients' clinical characteristics and prognosis were analyzed. Results: PD-1 was positive in 63.6%(56/88) NSCLC tumor tissues, which was significantly higher than that in adjacent normal tissues (21.6%, 19/88) (P<0.05). EGFR gene mutations were found in 43 cases (48.9%), in which 30 cases (69.8%)were PD-1 positive expression. 45 cases had the wild types of EGFR gene, in which 26 cases (57.8%) were PD-1 positive. There were 24 cases of 19Del EGFR mutations, including 20 cases (83.3%) of PD-1 positive expression. 19 patients had 21L858 EGFR mutations, including 10 cases (52.6%) of PD-1 positive expression. The expression of PD-1 in NSCLC was related to patients' smoking status, lymph node metastasis and EGFR gene mutations (P<0.05). The median progression-free survival time of patients with PD-1 positive and negative expression was 7.03 and 18.66 months, respectively (P=0.007). In patients with wild-type EGFR gene, the median progression-free survival time of PD-1 positive and negative expression was 25.21 and 38.24 months, respectively. The difference was statistically significant (P=0.024). The median progression-free survival time in 43 cases of EGFR mutant patients with PD-1 positive and negative expression was 21.23 and 31.44 months. The difference was not statistically significant (P=0.128). Conclusions: PD-1 expresses in both EGFR mutant and wild-type NSCLC, and its expression levelis different with various EGFR mutations. The expression of PD-1 in NSCLC is related to the prognosis of patients, and the prognosis of patients with positive PD-1 expression was poor.

Simultaneous overactivation of Wnt/\u03b2-catenin and TGF\u03b2 signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC

Cancer chemoresistance and metastasis are tightly associated features. However, whether they share common molecular mechanisms and thus can be targeted with one common strategy remain unclear in non-small cell lung cancer (NSCLC). Here, we report that high levels of microRNA-128-3p (miR-128-3p) is key to concomitant development of chemoresistance and metastasis in residual NSCLC cells having survived repeated chemotherapy and correlates with chemoresistance, aggressiveness and poor prognosis in NSCLC patients. Mechanistically, miR-128-3p induces mesenchymal and stemness-like properties through downregulating multiple inhibitors of Wnt/β-catenin and TGF-β pathways, leading to their overactivation. Importantly, antagonism of miR-128-3p potently reverses metastasis and chemoresistance of highly malignant NSCLC cells, which could be completely reversed by restoring Wnt/β-catenin and TGF-β activities. Notably, correlations among miR-128-3p levels, activated β-catenin and TGF-β signalling, and pro-epithelial-to-mesenchymal transition/pro-metastatic protein levels are validated in NSCLC patient specimens. These findings suggest that miR-128-3p might be a potential target against both metastasis and chemoresistance in NSCLC.

Overexpression of lncRNA HOXA11-AS promotes cell epithelial\u2013mesenchymal transition by repressing miR-200b in non-small cell lung cancer

BackgroundRecent studies have verified that long noncoding RNAs (lncRNAs) involved in many biological functions and play crucial roles in human cancers progression, the study aimed to detect the association between long non-coding RNA HOXA11-AS and epithelial–mesenchymal transition (EMT) process in non-small cell lung cancer (NSCLC).MethodsThe lncRNA HOXA11-AS expression levels were determined by quantitative real-time polymerase chain reaction (qRT-PCR) assays in 78 paired of tumor tissue and adjacent normal tissue samples in NSCLC patients. Kaplan–Meier survival curves and log-rank test was used to examine the association between lncRNA HOXA11-AS expression and the over survival time in NSCLC patients. Transwell invasion assay was performed to detect the cell invasion ability. QRT-PCR and western-blot analysis detected the mRNA and protein expression of EMT related transcription factors ZEB1/ZEB2, Snail1/2 and EMT marker E-cadherin and N-cadherin in NSCLC cells. RIP and Chromatin immunoprecipitation assays were performed to analyze the association between lncRNA HOXA11-AS and miR-200b expression in NSCLC cells.ResultsThe lncRNA HOXA11-AS expression levels were significantly higher in NSCLC tissues compared with adjacent normal tissues and higher HOXA11-AS expression levels had a poor prognosis in NSCLC patients. Furthermore, knockdown of lncRNA HOXA11-AS in A549 and H1299 cells dramatically inhibited cell invasive abilities. Besides, the transcription levels and protein levels of EMT related transcription factors ZEB1/ZEB2, Snail1/2, and EMT maker N-cadherin were down-regulated after lncRNA HOXA11-AS was knocked down, but the mRNA and protein expression levels of EMT maker E-cadherin was increasing in A549 and H1299 cells. The mechanistic findings showed demonstrated that HOXA11-AS interacted with EZH2 and DNMT1 and recruited them to the miR-200b promoter regions to repress miR-200b expression in NSCLC cells, which promoted cell EMT in NSCLC.ConclusionsOur results showed that up-regulation of lncRNA HOXA11-AS predicted a poor prognosis and lncRNA HOXA11-AS promoted cell epithelial–mesenchymal transition (EMT) by inhibiting miR-200b expression in NSCLC.

Serum dickkopf-1 as a clinical and prognostic factor in non-small cell lung cancer patients with bone metastases.

BackgroundThe study was designed to evaluate the association between serum dickkopf-1 (DKK1) and non-small cell lung cancer (NSCLC) bone metastases.Materials and MethodsSerum DKK1 levels were quantified in 470 NSCLC patients, 140 with osseous metastases, 178 with extraosseous metastases, and 152 with early stage in complete remission. The Receiver Operating Characteristic (ROC) curve enabled us to identify a threshold value to distinguish patients with bone metastases.ResultsSerum DKK1 levels in patients with osseous metastases were significantly higher than in the other 2 groups (P < 0.001). ROC curves showed that the optimum cutoff was 311.8 pg/ml (area under curve 0.791, 95% confidence interval 0.739–0.843, sensitivity 77.1% and specificity 71.4%). Of interest, serum DKK1 correlated with the number of bone lesions (P = 0.042) and associated with the poor survival in NSCLC patients with osseous metastases (P = 0.029).ConclusionsOur data shows that serum DKK1 can be used for the detection of NSCLC bone metastases. More importantly this is the first report to show that serum DKK1 is a good predictor of poor prognosis in NSCLC patients with bone metastases.

Evaluation of the 7th and 8th editions of the AJCC/UICC TNM staging systems for lung cancer in a large North American cohort.

PurposeThe new 8th American Joint Committee on Cancer (AJCC)/International Union for Cancer Control (UICC) lung cancer staging system was developed and internally validated using the International Association for the Study of Lung Cancer (IASLC) database, but external validation is needed. The goal of this study is to validate the discriminatory ability and prognostic performance of this new staging system in a larger, independent non-small cell lung cancer (NSCLC) cohort with greater emphasis on North American patients.MethodsA total of 858,909 NSCLC cases with one malignant primary tumor collected from 2004 to 2013 in the National Cancer Database (NCDB) were analyzed. The primary coding guidelines of the Collaborative Staging Manual and Coding Instructions for the new 8th edition AJCC/UICC lung cancer staging system was used to define the new T, M and TNM stages for all patients in the database. Kaplan-Meier curves, Cox regression models and time-dependent receiver operating characteristics were used to compare the discriminatory ability and prognostic performance of the 7th and the revised 8th T, M categories and overall stages.ResultsWe demonstrated that the 8th staging system provides better discriminatory ability than the 7th staging system and predicts prognosis for NSCLC patients using the NCDB. There were significant survival differences between adjacent groups defined by both clinical staging and pathologic staging systems. These staging parameters were significantly associated with survival after adjusting for other factors.ConclusionsThe updated T, M, and overall TNM stage of the 8th staging system show improvement compared to the 7th edition in discriminatory ability between adjacent subgroups and are independent predictors for prognosis.

Elevated pretreatment neutrophil/white blood cell ratio and monocyte/lymphocyte ratio predict poor survival in patients with curatively resected non-small cell lung cancer: Results from a large cohort.

BackgroundThe prognostic values of preoperative neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), and platelet/lymphocyte ratio (PLR) in non‐small cell lung cancer (NSCLC) have been previously described. This study assessed the prognostic values of other pretreatment complete blood cell parameters in Chinese patients with curatively resected NSCLC.MethodsA total of 1466 consecutive NSCLC patients who received curative surgery from January 1, 2005 to December 31, 2009 with complete data from pretreatment blood tests were enrolled in this retrospective study. Correlations between each blood test parameter and overall survival were examined by Kaplan–Meier method or Cox proportional hazards regression, followed by a stratification analysis of significant variables.ResultsOptimal cut‐off values of 0.55 for neutrophil/white blood cell ratio (NWR), 0.28 for lymphocyte/white blood cell ratio (LWR), 0.09 for monocyte/white blood cell ratio (MWR), 2.06 for NLR, 0.35 for MLR, 204.00 for PLR, and 38.25 for platelet/white blood cell ratio (PWR) were identified using X‐tile software. Univariate analysis suggested that NWR ≥ 0.55, LWR < 0.28, MWR ≥ 0.09, NLR ≥ 2.06, MLR ≥ 0.35, and PLR ≥ 204.00 predicted a poor prognosis in NSCLC patients. However, only NWR and MLR were identified as independent significant prognostic factors in multivariable analysis, especially in tumor node metastasis stage I and I/II/III NSCLCs.ConclusionPretreatment NWR, MWR, LWR, NLR, MLR, and PLR values are associated with poor overall survival for patients with curatively resected NSCLC. NWR and MLR are independent prognostic factors in curatively resected NSCLC.

DISC1 overexpression promotes non-small cell lung cancer cell proliferation

Neuropsychiatric disorder-associated disrupted-in-schizophrenia-1 (DISC1) activates Wnt/β-catenin signaling by inhibiting glycogen synthase kinase 3 beta (GSK3β) phosphorylation, and may promote neural progenitor cell and pancreatic β-cell proliferation. The present study found that DISC1 promotes non-small cell lung cancer (NSCLC) cell growth. Western blotting and immunohistochemistry analyses showed that DISC1 was highly expressed in NSCLC cell lines and patient tissues. DISC1 expression was negatively associated with phosphorylated (p-) GSK3β, but positively correlated with a more invasive tumor phenotype and predicted poor NSCLC patient prognosis. siRNA-mediated DISC1 silencing increased p-GSK3β expression and decreased expression of β-catenin and Cyclin D1, while DISC1 upregulation produced the opposite results. DISC1 knockdown also reduced NSCLC cell proliferation rates in vitro. These results suggest that DISC1 promotes NSCLC growth, likely through GSK3β/β-catenin signaling, and that DISC1 may function as an oncogene and novel anti-NSCLC therapeutic target.

Hyponatraemia as an unrecognised risk factor in non-small cell lung cancer (NSCLC) treatment with nivolumab.

e14526 Background: The investigation, diagnosis and management of hyponatraemia is often inadequate in cancer patients. In a retrospective analysis of 3,357 cancer patients hyponatraemia was noted in up to 47%. A strong and independent association between hyponatremia and longer length of stay with higher mortality was highlighted and associated with standard chemotherapy. No pooled data, however are available on the effect of immuno-oncology (IO) treatment options such as nivolumab on HN in lung cancer patients. Methods: Key publications and data registries concerning the incidence, evaluation and management of hyponatraemia in patients with NSCLC and treated with nivolumab were analysed. Our data show that hyponatraemia is a common side effect and around 5.2% of patients treated with nivolumab progressed from baseline to a Grade 3 / 4 adverse event. Results: The aetiology of hyponatraemia in cancer patients is complex, appearing to be a negative prognostic indicator. Existing data show that effective treatment of hyponatraemia in cancer patients may be associated with reduced mortality. In addition, the role of sodium on the cancer cell cycle requires further investigation. It has been shown in vitro that a hypotonic environment is pro-tumorigenic, whereas a slightly hypertonic environment may have a negative impact on clonogenicity in prostate cancer cells. This may suggest a more complex interaction impacting on cancer patients other than a simplistic mortality association with hyponatraemia. Nivolumab treatment is associated with HN and particular attention should be paid to the correction of symptomatic HN in these patients. Conclusions: Hyponatraemia is the most commonly occurring electrolyte disturbance in cancer patients and may represent a modifiable risk factor impacting patient survival. The clinician should be aware of the potential for IO therapies to precipitate hyponatraemia. Consideration of the correct diagnosis and management of hyponatraemia may further enhance the prognosis of NSCLC patients treated with IO agents.

MicroRNA-92a promotes epithelial-mesenchymal transition through activation of PTEN/PI3K/AKT signaling pathway in non-small cell lung cancer metastasis.

MicroRNAs (miRNAs) have important roles in various cancers, including non-small cell lung cancer (NSCLC). Although several miRNAs have reported to be involved in the development of NSCLC, understanding the regulatory roles of other miRNAs in NSCLC is essential. Therefore, the aim of the current study was to explore the roles and mechanisms of screened miRNAs in NSCLC. First, the differentially expressed miRNAs that were screened based on GSE29248 microarray data retrieved from Gene Expression Omnibus (GEO). The expression of miR-92a, acted as an oncogene in many cancers, was validated using quantitative real-time PCR (qRT-PCR), and then its association with overall survival was analyzed. The efficacy of miR-92a to promote cell proliferation, invasion and metastasis was evaluated invitro, and invivo. Then, the role of miR-92a in epithelial-mesenchymal transition (EMT), a key step of the progression of tumor cell metastasis, was investigated in NSCLC cells. The association of miR-92a and its downstream target was investigated in both cell line and clinical specimens. Furthermore, gain- and loss-of-function studies of the phosphatase and tensin homolog (PTEN) were performed to assess whether the effect of miR-92a promoted growth and metastasis of NSCLC cells were via targeting PTEN. Our results showed that miR-92a was significantly upregulated in NSCLC tissues and NSCLC cell lines, and was positively associated with poor prognosis of NSCLC patients. The overexpression of miR-92a enhanced EMT-relatived protein levels, promoted NSCLC cell migration and invasion invitro, and increased tumor growth invivo. Bioinformatic prediction and function assay suggested that PTEN, a negative regulator of PI3K/AKT pathway, was a direct target of miR-92a. It was found that PTEN expression was inversely correlated with miR-92a in NSCLC tissues. In addition, miR-92a could activate the PI3K/AKT pathway by inhibiting PTEN expression. Notably, Transwell and wound healing assays demonstrated that altering PTEN expression abrogated the promotive effects of miR-92a on NSCLC cell migration and invasion. Taken together, these results demonstrated that miR-92a induced EMT and regulated cell migration and invasion in the NSCLC cells through regulating PI3K/AKT signaling pathway by targeting PTEN, indicating that miR-92a may be an attractive target and prognostic marker for NSCLC.

RASSF1A and SIRT6 in non-small cell lung cancer: Relationship with clinical outcome.

This study investigated the expression of RASSF1A and SIRT6 in non-small cell lung cancer (NSCLC) and its relationship with clinical prognosis. The expression in 122 cases of NSCLC tissues (NSCLC group) and 122 cases of normal lung tissues (NOR group) during the same period were detected by immunohistochemical Super Pic Ture™ Polymer two-step method, and the relationship between its expression and the clinicopathological features and prognosis of patients was analyzed. The positive expression rates of RASSF1A and SIRT6 in NSCLC group were lower than those in the normal group (55.74 vs. 84.43% and 52.46 vs. 82.49%, P<0.01). The differences in expression intensity of RASSF1A in NSCLC tissues between different tumor pathological types, tumor differentiation degrees and lymph node metastases were statistically significant, and the differences in expression intensity of SIRT6 between different TNM stages, tumor differentiation degrees and lymph node metastases were statistically significant. There was a positive correlation between the expression of RASSF1A and SIRT6 in NSCLC group (r=0.532, P<0.01). The 3-year survival rate of patients with high-expression of RASSF1A was higher than in those with low-expression of RASSF1A (81.33 vs. 39.45%, log-rank χ2=19,102, P<0.01); the 3-year survival rate of patients with high-expression of SIRT6 was higher than in those with low-expression of SIRT6 (83.51 vs. 42.43%, log-rank χ2=17,180, P<0.01). The low expression of RASSF1A and SIRT6 and lymph node metastasis were the risk factors affecting the prognosis of NSCLC patients. There is a better correlation between the expression of RASSF1A and SIRT6 in NSCLC tissues, and the detection of their expression is of great significance in the judgement of clinicopathological features and prognosis of NSCLC patients.

Dual-negative expression of Nrf2 and NQO1 predicts superior outcomes in patients with non-small cell lung cancer.

Functional studies in non-small cell lung cancer (NSCLC) patients revealed that hyperactivation of the NF-E2-related factor 2 (Nrf2) pathway facilitates tumor growth. We examined the usefulness of Nrf2 and NQO1 as indicators of prognosis in NSCLC. Tumor and adjacent non-tumor tissue samples were collected from 215 NSCLC patients who had tumor resections between 2006 and 2011. Immunohistochemistry was performed to detect Nrf2 or NQO1 expression. The correlation between Nrf2 or NQO1 expression and survival outcomes was evaluated using the Kaplan-Meier method and Cox proportional hazards regression model. Levels of Nrf2 and NQO1 were elevated in tumor tissues. In particular, Nrf2 was elevated in nearly all tumor cells. NQO1 expression positively correlated with Nrf2 expression (P = 0.039). Nrf2 expression positively correlated with lymph node metastasis (P = 0.001) and negatively correlated with tumor differentiation (P = 0.032). As compared with either Nrf2 or NQO1 alone, dual-negative expression of Nrf2 and NQO1 was more predictive of superior overall survival (P = 0.020) and disease free survival (P = 0.037). Subgroup analyses showed that females, nonsmokers, and patients with advanced-stage NSCLC were suitable populations in which to evaluate prognosis based on Nrf2 and NQO1 co-expression. These results indicate that dual-negative expression of Nrf2 and NQO1 is predictive of a better prognosis in NSCLC patients.

Targeting CCR2 with its antagonist suppresses viability, motility and invasion by downregulating MMP-9 expression in non-small cell lung cancer cells.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, which is the leading cancer killer in the world. Despite the recent advances in its diagnosis and therapy, the prognosis of NSCLC patients remains very poor, mainly due to the development of drug resistance and metastasis. Both the chemokine network and the matrix metalloproteinase (MMP) system play important roles in cancer cell metastasis. The disruption of CCL2/CCR2 chemokine signaling has been shown to suppress cancer cellviability and metastasis. CCL2-neutralizing antibodies, which have shown promising therapeutic efficacy in several cancer models, are not widely used due to technical issues. CCR2 antagonism has thus become an alternative method for cancer treatment. However, the effect of CCR2 antagonists on NSCLC progression remains poorly understood. Here, we investigated the effect of CCR2 antagonist (CAS445479-97-0) on the proliferation, migration and invasion of human lung adenocarcinoma A549 cells by using WST-1 cell viability assay, transwell migration assay, wound healing scratch assay and Matrigel invasion assay. We demonstrated that CCL2 treatment promoted A549 cell viability, motility and invasion by upregulating MMP-9 expression and that this induction was significantly suppressed by CAS 445479-97-0. Taken together, our data suggested that the CCR2 antagonist would be a potential drug for treating CCR2-positive NSCLC patients.

Mesenchymal circulating tumor cells (CTCs) and OCT4 mRNA expression in CTCs for prognosis prediction in patients with non-small-cell lung cancer.

Circulating tumor cells (CTCs) with epithelial-to-mesenchymal transition (EMT) phenotypes might be related to tumor progression while OCT4 expression is involved in tumor metastasis and poor prognosis. But the possible clinical significance of EMT phenotypes of CTCs from non-small-cell lung cancer (NSCLC) patients has still to be demonstrated. Furthermore, none has been investigated the expression of OCT4 in CTCs. We therefore identified the EMT phenotype-based subsets of CTCs and determined the OCT4 expression status of CTCs in NSCLC patients, to explore their possible clinical relevance. 37 NSCLC patients and ten healthy volunteers were enrolled, respectively. The Canpatrol™ CTC enrichment technique was used to isolate and identify the EMT phenotype-based subsets of CTCs. OCT4 expression in each CTC was also determined. Results were correlated with patients' clinico-pathological features. CTCs were detected in 33 of 37 (89.2%) NSCLC patients, and no CTCs were identified in ten healthy volunteers. Three CTCs phenotypes, including epithelial, biophenotypic, and mesenchymal CTCs were identified based on the expression of EMT markers. Mesenchymal CTCs were more commonly found in patients with distant metastasis. Patients with distant metastasis tended to have a higher median CTCs number. OCT4-positive was observed in 21 of 28 (75.0%) patients. High expression of OCT4 tended to occur in advanced patients as well as in distant metastatic patients. The findings suggest that identification of CTCs by EMT markers as well as evaluation of OCT4 expression status by assessment of OCT4 expression in CTCs could serve as potential adjuncts for evaluating metastasis and prognosis in NSCLC patients.

Mining expression and prognosis of topoisomerase isoforms in non-small-cell lung cancer by using Oncomine and Kaplan-Meier plotter.

DNA topoisomerases are essential to modulate DNA topology during various cellular genetic processes. The expression and distinct prognostic value of topoisomerase isoforms in non-small-cell lung cancer (NSCLC) is not well established. In the current study, we have examined the mRNA expression of topoisomerase isoforms by using Oncomine analysis and investigated their prognostic value via the Kaplan–Meier plotter database in NSCLC patients. Our analysis indicated that the expression level of topoisomerases in lung cancer was higher compared with normal tissues. Especially, high expression of two topoisomerase isoforms, TOP2A and TOP3A, was found to be correlated to worse overall survival (OS) in all NSCLC and lung adenocarcinoma (Ade) patients, but not in lung squamous cell carcinoma (SCC) patients. In a contrast, high expression of isoforms TOP1 and TOP2B indicated better OS in all NSCLC and Ade, but not in SCC patients. Meanwhile, high expression of TOP1MT and TOP3B was not correlated with OS in NSCLC patients. Furthermore, we also demonstrated a relationship between topoisomerase isoforms and the clinicopathological features for the NSCLC patients, such as grades, clinical stages, lymph node status, smoking status, gender, chemotherapy and radiotherapy. These results support that TOP2A and TOP3A are associated with worse prognosis in NSCLC patients. In addition, our study also shows that TOP1 and TOP2B contribute to favorable prognosis in NSCLC patients. The exact prognostic significance of TOP1MT and TOP3B need to be further elucidated. Comprehensive evaluation of expression and prognosis of topoisomerase isoforms will be a benefit for the better understanding of heterogeneity and complexity in the molecular biology of NSCLC, paving a way for more accurate prediction of prognosis and discovery of potential drug targets for NSCLC patients.

Prognostic role of B7-H4 in patients with non-small cell lung cancer: A meta-analysis.

B7 homolog 4 (B7-H4) has been recently reported to be a prognostic marker in non-small cell lung cancer (NSCLC) in some studies. However, the results remained conflicting. Thus, we aimed to comprehensively assess the association between B7-H4 expression and prognosis of NSCLC patients by performing a meta-analysis. Relevant publications were thoroughly searched of PubMed, Embase, Web of Science and China National Knowledge Infrastructure (CNKI). The pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were applied to evaluate the effects. A total of 9 studies comprising 1444 patients were included in this meta-analysis. B7-H4 overexpression was associated with presence of lymph node metastasis (OR=3.59, 95%CI=2.39-5.38, p<0.001; fixed effect), advanced TNM stage (OR=2.36, 95%CI=1.2-4.67, p=0.013; random effect), and poor differentiation (OR=2.11, 95%CI=1.12-3.99, p=0.021; fixed effect). However, B7-H4 had no significant correlation with gender, age or histology in NSCLC. Furthermore, in a fixed effects model, the results indicated that B7-H4 overexpression was significantly associated with poor OS (HR=2.03, 95%CI=1.41-2.92, p<0.001). This meta-analysis demonstrated that high B7-H4 expression is an unfavorable prognostic factor in NSCLC. Because few studies were included for meta-analysis and almost all included studies were performed on Chinese patients, therefore; large scale prospective studies are needed to verify our results.

Amino acid transporter SLC38A3 promotes metastasis of non-small cell lung cancer cells by activating PDK1

BackgroundTumor metastasis is a finely-tuned pathological process coupled to metabolic reprogramming that includes both glutamine and glucose. The solute carrier SLC38A3, a member of amino acid/polyamine/organocation (APC) superfamily, is an l-glutamine transporter. It is not clear whether SLC38A3 involves the metastasis of NSCLC (non small cell lung cancer). MethodsThe scratch test and transwell assay were used to determine the ability of NSCLC to migrate. Cellular amino acids content was determined by mass spectrometry. The cellular response to glutamine/histidine deficiency was evaluated in A549 cells. The expression of SLC38A3 was assayed in clinical NSCLC and paratumor tissues by histoimmunochemistry staining. A nude mouse model of NSCLC metastasis was developed by tail vein injection of tumor cells. ResultsSLC38A3 was upregulated in metastatic NSCLC cells and its expression was correlated with prognosis of NSCLC patients. SLC38A3 overexpression promoted epithelial – mesenchymal transition (EMT) and migration of HCC827 and A549 human lung adenocarcinoma cells, and accelerated tumor metastasis in mice. We found that SLC38A3 decreased the cellular concentrations of glutamine and histidine, and the deficiency of glutamine or histidine activated PDK1/AKT signaling that in turn, triggered NSCLC metastasis. ConclusionsSLC38A3 activated PDK1/AKT signaling and promoted metastasis of NSCLC through regulating glutamine and histidine transport, suggesting SLC38A3 as a potential therapeutic target for treatment of NSCLC.

MiR-367 promotes tumor growth by inhibiting FBXW7 in NSCLC.

miR-367 is one of the most abundant miRNAs in human embryonic stem cells (hESCs) and is mainly involved in maintaining the pluripotency of stem cells. However, its role in cancer development remains poorly understood. In the present study, we explored the function and mechanism of the endogenous miR-367 in non-small cell lung cancer (NSCLC). In the present study, we demonstrated that the level of miR-367 in NSCLC was significantly higher than that in adjacent normal tissues, and its upregulation was positively correlated with tumor size, tumor differentiation and tumor-node-metastasis (TNM) stage. miR-367 was an indicator of a poorer prognosis in NSCLC patients. Furthermore, overexpression of miR-367 significantly inhibited apoptosis and enhanced proliferation by promoting cell cycle transition from G1 to Sphase. In contrast, knockdown of miR-367 markedly reversed the cellular events observed with miR-367 overexpression. Moreover, we identified that F-box and WD repeat domain-containing7 (FBXW7) is a novel target of miR-367. It reverses the oncogenic effects of miR-367 by downregulating its substrates, c-Myc and c-Jun, in NSCLC cells. Finally, studies invivo revealed that knockdown of miR-367 inhibited the growth of xenografts in the nude mice by increasing the expression of FBXW7. In summary, our findings indicate that miR-367 exerts tumor-promoting effect by negatively regulating FBXW7 in NSCLC, and it could become a potential therapeutic target for NSCLC intervention.

Prognostic significance of serum chemerin levels in patients with non-small cell lung cancer.

Chemerin plays an important role in adipogenesis and chemotaxis of the innate immune system. The aim of this study was to explore the significance and prognostic value of serum chemerin levels in patients with non-small cell lung cancer (NSCLC). Serum specimens from 189 NSCLC patients and 120 healthy controls were collected. The levels of serum chemerin were measured by sandwich enzyme-linked immunosorbent assay (ELISA). The serum chemerin levels were significantly elevated in NSCLC patients compared with healthy controls (P < 0.001). Higher serum chemerin levels were associated with advanced TNM stage, lymph node metastasis, and distant metastasis. Area under receiver operating characteristic curve (ROC) for serum chemerin was 0.809 (95% CI: 0.722–0.896) at a sensitivity of 0.624 and of specificity 0.675. The cut-off value of chemerin was 1500 pg/ml for discriminating NSCLC from healthy controls. Kaplan-Meier log rank analysis revealed that the higher serum chemerin patients had a shorter overall survival (OS) and progression-free survival (PFS) compared with lower chemerin patients (P = 0.004, P = 0.001, respectively). Further univariate and multivariate Cox regression analysis showed that serum chemerin was an independent risk factor of prognosis of NSCLC patients. In conclusion, measurement of chemerin might be a useful diagnostic and prognostic biomarker for NSCLC patients.

Supraclavicular lymph node incisional biopsies have no influence on the prognosis of advanced non-small cell lung cancer patients: a retrospective study

BackgroundSupraclavicular lymph node (SCLN) biopsies play an important role in diagnosing and staging lung cancer. However, not all patients with SCLN metastasis can have a complete resection. It is still unknown whether SCLN incisional biopsies affect the prognosis of non-small cell lung cancer (NSCLC) patients.MethodsPatients who were histologically confirmed to have NSCLC with SCLN metastasis were enrolled in the study from January 2007 to December 2012 at Guangdong Lung Cancer Institute. The primary endpoint was OS, and the secondary endpoints were complications and local recurrence/progression.ResultsTwo hundred two consecutive patients who had histologically confirmed NSCLC with SCLN metastasis were identified, 163 with excisional and 39 with incisional biopsies. The median OS was not significantly different between the excisional (10.9 months, 95% CI 8.7–13.2) and incisional biopsy groups (10.1 months, 95% CI 6.3–13.9), P = 0.569. Multivariable analysis showed that an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 (HR = 2.75, 95% CI 1.71–4.38, P < 0.001) indicated a worse prognosis. Having an epidermal growth factor receptor (EGFR) mutation (HR = 0.58, 95% CI 0.40–0.84, P = 0.004) and receiving systemic treatment (HR = 0.36, 95% CI 0.25–0.53, P < 0.001) were associated with a favorable OS. Neither the number (multiple vs. single) nor site (bilateral vs. unilateral) of SCLNs was associated with an unfavorable OS, and SCLN size or fixed SCLNs did not affect OS.ConclusionsSCLN incisional biopsies did not negatively influence the prognosis of NSCLC patients. It was safe and feasible to partly remove a metastatic SCLN as a last resort in advanced NSCLC.