BACKGROUND: Currently, lung cancer is one of the malignant tumors with a high morbidity and mortality all over the world. However, the exact mechanisms underlying lung cancer progression remain unclear. The tumor necrosis factor receptor associated factor (TRAF) family members are cytoplasmic adaptor proteins, which function as both adaptor proteins and ubiquitin ligases to regulate diverse receptor signalings, leading to the activation of nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK) and interferon regulatory factor (IRF) signaling. The aim of this study was to investigate the expression of TRAFs in different tissues and cancer types, as well as its mRNA expression, protein expression, prognostic significance and functional enrichment analysis in non-small cell lung cancer (NSCLC), in order to provide new strategies for the diagnosis and treatment of NSCLC. METHODS: RNA sequencing data from the The Genotype-Tissue Expression database was used to analyze the expression patterns of TRAF family members in different human tissues. RNA sequencing data from the Cancer Cell Line Encyclopedia database was used to analyze the expression patterns of TRAF family members in different types of cancer cell lines. RNA sequencing data from the The Cancer Genome Atlas (TCGA) database was used to analyze the mRNA levels of TRAF family members across different types of human cancers. Immunohistochemistry (IHC) analyses from HPA database were used to analyze the TRAF protein levels in NSCLC [lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC)]. Overall survival analysis was performed by Log-rank test using original data from Kaplan-Meier Plotter database to evaluate the correlation between TRAF expressions and prognosis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed on the TRAF family-related genes using RNA sequencing data from the TCGA database for NSCLC. The correlation between the expression levels of TRAF family members and the tumor immune microenvironment was analyzed using the ESTIMATE algorithm based on RNA sequencing data from the TCGA database. RESULTS: The TRAF family members exhibited significant tissue-specific expression heterogeneity. TRAF2, TRAF3, TRAF6 and TRAF7 were widely expressed in most tissues, while the expressions of TRAF1, TRAF4 and TRAF5 were restricted to specific tissues. The expressions of TRAF family members were highly specific among different types of cancer cell lines. In mRNA database of LUAD and LUSC, the expressions of TRAF2, TRAF4, TRAF5 and TRAF7 were significantly upregulated; while TRAF6 did the opposite; moveover, TRAF1 and TRAF3 only displayed a significant upregulation in LUAD and LUSC, respectively. Except for TRAF3, TRAF4 and TRAF7, other TRAF proteins displayed an obviously deeper IHC staining in LUAD and LUSC tissues compared with normal tissues. Additionally, patients with higher expression levels of TRAF2, TRAF4 and TRAF7 had shorter overall survival; while patients with higher expression levels of TRAF3, TRAF5 and TRAF6 had significantly longer overall survival; however, no significant difference had been observed between TRAF1 expression and the overall survival. TRAF family members differentially regulated multiple pathways, including NF-κB, immune response, cell adhesion and RNA splicing. The expression levels of TRAF family members were closely associated with immune cell infiltration and stromal cell content in the tumor immune microenvironment, with varying positive and negative correlations among different members. CONCLUSIONS TRAF family members exhibit highly specific expression differences across different tissues and cancer types. Most TRAF proteins exhibit upregulation at both mRNA and protein levels in NSCLC, whereas, only upregulated expressions of TRAF2, TRAF4 and TRAF7 predict worse prognosis. The TRAF family members regulate processes such as inflammation, immunity, adhesion and splicing, and influence the tumor immune microenvironment.
Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Lung Neoplasms/mortality* ; Prognosis ; Gene Expression Regulation, Neoplastic ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/metabolism*

BACKGROUND: The purpose of this study is to compare the survival time of non-small cell lung cancer (NSCLC) patients with different organ metastasis. Among all cancers, the morbidity and mortality of lung cancer is the highest worldwide, which may caused by local recurrence and distant metastasis, and the location of metastasis may predict the prognosis of patients. METHODS: A total of 117,542 patients with NSCLC diagnosed between 2010 and 2014 were enrolled from Surveillance, Epidemiology, and End Result (SEER) databases, and the relationship between distant metastasis and survival time was retrospectively analyzed. RESULTS: Of all the 117,542 patients diagnosed with non-small cell lung cancer, 42,071 (35.8%) patients had different degrees of distant metastasis during their medical history, including 26,932 single organ metastases and 15,139 multiple organ metastases, accounting for 64.0% and 36.0% of the metastatic patients respectively. Compared with patients with no metastasis, whose median survival time was 21 months, the median survival time of patients with metastases was 7 months (lung), 6 months (brain), 5 months (bone), 4 months (liver), and 3 months (multiple organ) respectively, and the difference was significant (P<0.001, except liver vs multiple organ P=0.650); Most patients with NSCLC (88.4%) eventually died of lung cancer. CONCLUSIONS Distant metastasis of NSCLC patients indicates poor prognosis. In NSCLC patients with single organ metastasis, the prognosis of lung metastasis is the best, and liver metastasis is the worst, and multiple organ metastasis is worse than single organ metastasis.
Aged ; Aged, 80 and over ; Bone Neoplasms ; mortality ; secondary ; Brain Neoplasms ; mortality ; secondary ; Carcinoma, Non-Small-Cell Lung ; mortality ; pathology ; Female ; Humans ; Liver Neoplasms ; mortality ; secondary ; Lung Neoplasms ; mortality ; pathology ; Male ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Staging ; Prognosis ; Retrospective Studies

BACKGROUND: Currently, there is no consensus on the follow-up strategy (follow-up time interval and content) of non-small cell lung cancer (NSCLC) in the world, and the relevant clinical evidence is also very limited. In this study, we aimed to summarize the recurrence/metastasis sites and timings of stage I NSCLC patients based on their follow-up data, aiming to provide a basis of follow-up time interval and content for this group of patients. METHODS: We retrospectively analyzed the 416 stage I NSCLC patients that underwent continuous anatomic lobectomy between Jan. 2000 to Oct. 2013 in our prospective lung cancer database. According to the recurrence/metastasis sites and timings, the long term follow-up time interval and content were explored. RESULTS: The 5-yr disease free survival (DFS) and overall survival (OS) in the whole group were 82.4% and 85.4%, respectively. There were 76 cases (18.3%) had recurrence/metastasis during follow-up, among which the most frequent site was pulmonary metastasis (21 cases, 5.0%), followed by brain metastasis (20 cases, 4.8%), bone metastasis (12 cases, 2.9%), and mediastinal lymph node metastasis (12 cases, 2.9%). Among the factors that could influence recurrence/metastasis, patients with pT2a suffered from a higher recurrence/metastasis rate compared to patients with pT1 (P=0.006), with 5-yr DFS being 73.8% and 87.3%, respectively (P=0.002), and the 5-yr OS being 77.7% and 90.3%, respectively (P=0.011). CONCLUSIONS The commonest recurrence/metastasis sites of stage I NSCLC after anatomic lobectomy are lung, brain and mediastinal lymph nodes, the risk of recurrence/metastasis within 2 years were equal to that between 3 years and 5 years. The follow-up frequencies and content within 2 years could be adjusted according to T stages.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Non-Small-Cell Lung ; mortality ; pathology ; surgery ; Female ; Follow-Up Studies ; Humans ; Lung Neoplasms ; mortality ; pathology ; surgery ; Lymph Nodes ; surgery ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Pneumonectomy ; Prospective Studies ; Retrospective Studies ; Young Adult

OBJECTIVETo review the prevalence and prognostic significance of fibroblast growth factor receptor 1 (FGFR1) amplification and to establish an association between FGFR1 amplification and the clinical characteristics of nonsmall cell lung cancer (NSCLC).

DATA SOURCESWe searched PubMed for English-language studies published between January 2010 and May 2016.

STUDY SELECTIONWe included all relevant articles, with no limitation of study design.

RESULTSFGFR1 amplification was reported in 8.7-20.0% of NSCLC cases and was significantly more frequent in squamous cell carcinomas (SCCs) (9.7-28.3%) than in adenocarcinomas (ADCs) (0-15.0%). The rates of FGFR1 amplification were as follows: males, 13.9-22.1%; females, 0-20.1%; Stage I NSCLC, 9.3-24.1%; Stage II NSCLC, 12.9-25.0%; Stage III NSCLC, 8.2-19.5%; Stage IV NSCLC, 0-12.5%; current smokers, 13.3-29.0%; former smokers, 2.5-23.0%; and nonsmokers, 0-22.2%. Overall survival was 43.9-70.8 months in patients with FGFR1 amplification and 42.4-115.0 months in patients with no FGFR1 amplification; disease-free survival was 22.5-58.5 months and 52.4-94.6 months, respectively.

CONCLUSIONSFGFR1 amplification is more frequent in SCCs than in ADCs. The association between FGFR1 amplification and clinical characteristics (gender, smoking status, and disease stage) and the prognostic significance of FGFR1 amplification in NSCLC remain controversial.

Adenocarcinoma ; genetics ; mortality ; pathology ; Carcinoma, Non-Small-Cell Lung ; genetics ; mortality ; pathology ; Carcinoma, Squamous Cell ; genetics ; mortality ; pathology ; Disease-Free Survival ; Female ; Gene Amplification ; genetics ; Humans ; Male ; Receptor, Fibroblast Growth Factor, Type 1 ; genetics

Hypoxia-inducible factor-1 alpha (HIF-1α) plays a vital role in the initiation, evaluation and prognosis in lung cancer. The prognostic value of HIF-1α reported in diverse study remains disputable. Accordingly, a meta-analysis was implemented to further understand the prognostic role of HIF-1α in lung cancer. The relationship between HIF-1α and the clinicopathological characteristics and prognosis of lung cancer were investigated by a meta-analysis. PubMed and Embase were searched from their inception to January 2015 for observational studies. Fixed-effects or random-effects meta-analyses were used to calculate odds ratios and 95% confidence intervals of different comparisons. A total of 20 studies met the criteria. The results showed that HIF-1α expression in lung cancer tissues was significantly higher than that in normal lung tissues. Expression of HIF-1α in patients with squamous cell carcinoma was significantly higher than that of patients with adenocarcinomas. Similarly, non-small cell lung cancer (NSCLC) patients had higher HIF-1α expression than small cell lung cancer (SCLC) patients. Moreover, lymph node metastasized tissues had higher HIF-1α expression than non-lymph node metastasized tissues. A high level HIF-1α expression was well correlated with the expression of vascular endothelial growth factor and epidermal growth factor receptor in the NSCLC. Notably, NSCLC or SCLC patients with positive HIF-1α expression in tumor tissues had lower overall survival rate than patients with negative HIF-1α expression. It was suggested that HIF-1α expression may be a prognostic biomarker and a potential therapeutic target for lung cancer.
Adenocarcinoma ; diagnosis ; genetics ; mortality ; pathology ; Biomarkers, Tumor ; genetics ; metabolism ; Carcinoma, Non-Small-Cell Lung ; diagnosis ; genetics ; mortality ; pathology ; Carcinoma, Squamous Cell ; diagnosis ; genetics ; mortality ; pathology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; genetics ; metabolism ; Lung Neoplasms ; diagnosis ; genetics ; mortality ; pathology ; Lymphatic Metastasis ; Neoplasm Grading ; Neoplasm Staging ; Odds Ratio ; Prognosis ; Receptor, Epidermal Growth Factor ; genetics ; metabolism ; Survival Analysis ; Vascular Endothelial Growth Factor A ; genetics ; metabolism

BACKGROUNDIncreased level of serum macrophage inhibitory cytokine-1 (MIC-1), a member of transforming growth factor-μ superfamily, was found in patients with epithelial tumors. This study aimed to evaluate whether serum level of MIC-1 can be a candidate diagnostic and prognostic indicator for early-stage nonsmall cell lung cancer (NSCLC).

METHODSA prospective study enrolled 152 patients with Stage I-II NSCLC, who were followed up after surgical resection. Forty-eight patients with benign pulmonary disease (BPD) and 105 healthy controls were also included in the study. Serum MIC-1 levels were measured using an enzyme-linked immunosorbent assay, and the association with clinical and prognostic features was analyzed.

RESULTSIn patients with NSCLC, serum protein levels of MIC-1 were significantly increased compared with healthy controls and BPD patients (all P< 0.001). A threshold of 1000 pg/ml of MIC-1 was found in patients with early-stage (Stage I and II) NSCLC, with sensitivity and specificity of 70.4% and 99.0%, respectively. The serum levels of MIC-1 were associated with age (P = 0.001), gender (P = 0.030), and T stage (P = 0.022). Serum MIC-1 threshold of 1465 pg/ml was found in patients with poor early outcome, with sensitivity and specificity of 72.2% and 66.1%, respectively. The overall 3-year survival rate of NSCLC patients with high serum levels of MIC-1 (≥1465 pg/ml) was lower than that of NSCLC patients with low serum MIC-1 levels (77.6% vs. 94.8%). Multivariate Cox regression survival analysis showed that a high serum level of MIC-1 was an independent risk factor for reduced overall survival (hazard ratio = 3.37, 95% confidential interval: 1.09-10.42, P= 0.035).

CONCLUSIONThe present study suggested that serum MIC-1 may be a potential diagnostic and prognostic biomarker for patients with early-stage NSCLC.

Adult ; Aged ; Carcinoma, Non-Small-Cell Lung ; blood ; mortality ; pathology ; surgery ; Enzyme-Linked Immunosorbent Assay ; Female ; Growth Differentiation Factor 15 ; blood ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Proportional Hazards Models ; Prospective Studies ; Survival Rate

Recently, genetic variants in the WNT signaling pathway have been reported to affect the survival outcome of Caucasian patients with early stage non-small cell lung cancer (NSCLC). We therefore attempted to determine whether these same WNT signaling pathway gene variants had similar impacts on the survival outcome of NSCLC patients in a Korean population. A total of 761 patients with stages I-IIIA NSCLC were enrolled in this study. Eight variants of WNT pathway genes were genotyped and their association with overall survival and disease-free survival were analyzed. None of the eight variants were significantly associated with overall survival or disease-free survival. There were no differences in survival outcome after stratifying the subjects according to age, gender, smoking status, and histological type. These results suggest that genetic variants in the WNT signaling pathway may not affect the survival outcome of NSCLC in a Korean population.
Aged ; Asian Continental Ancestry Group/*genetics ; Carcinoma, Non-Small-Cell Lung/*genetics/mortality/pathology ; Demography ; Disease-Free Survival ; Female ; Genotype ; Humans ; Kaplan-Meier Estimate ; Lung Neoplasms/*genetics/mortality/pathology ; Male ; Middle Aged ; *Polymorphism, Single Nucleotide ; Republic of Korea ; Smoking ; Wnt Signaling Pathway/*genetics

PURPOSE: Patients with non-small cell lung cancer (NSCLC) and simultaneously having brain metastases at the initial diagnosis, presenting symptoms related brain metastasis, survived shorter duration and showed poor quality of life. We analyzed our experiences on surgical treatment of brain metastasis in patients with NSCLC. MATERIALS AND METHODS: We performed a single-center, retrospective review of 36 patients with NSCLC and synchronous brain metastases between April 2006 and December 2011. Patients were categorized according to the presence of neurological symptoms and having a brain surgery. As a result, 14 patients did not show neurological symptoms and 22 patients presented neurological symptoms. Symptomatic 22 patients were divided into two groups according to undergoing brain surgery (neurosurgery group; n=11, non-neurosurgery group; n=11). We analyzed overall surgery (OS), intracranial progression-free survival (PFS), and quality of life. RESULTS: Survival analysis showed there was no difference between patients with neurosurgery (OS, 12.1 months) and non-neurosurgery (OS, 10.2 months; p=0.550). Likewise for intracranial PFS, there was no significant difference between patients with neurosurgery (PFS, 6.3 months) and non-neurosurgery (PFS, 5.3 months; p=0.666). Reliable neurological one month follow up by the Medical Research Council neurological function evaluation scale were performed in symptomatic 22 patients. The scale improved in eight (73%) patients in the neurosurgery group, but only in three (27%) patients in the non-neurosurgery group (p=0.0495). CONCLUSION: Patients with NSCLC and synchronous brain metastases, presenting neurological symptoms showed no survival benefit from neurosurgical resection, although quality of life was improved due to early control of neurological symptoms.
Adult ; Aged ; Aged, 80 and over ; Brain Neoplasms/physiopathology/*secondary/*surgery ; Carcinoma, Non-Small-Cell Lung/mortality/*pathology ; Demography ; Disease-Free Survival ; Female ; Follow-Up Studies ; Humans ; Kaplan-Meier Estimate ; Lung Neoplasms/*pathology ; Male ; Middle Aged ; Treatment Outcome

This study aimed to explore Semaphrin4D (Sema4D) expression and clinical significance in non-small cell lung cancer (NSCLC), and to define the roles and mechanisms of Sema4D in regulating the malignant behaviors of A549 cells by small interfering RNA (siRNA). Firstly, immunohistochemistry revealed that Sema4D was more frequently expressed in NSCLC than in lung benign lesion (P<0.05) and its overexpression was associated with low differentiation (P<0.05), poor pTNM staging (P<0.05) and occurrence of lymph node (LN) metastasis (P<0.05). Endogenous Sema4D expression was suppressed by Sema4D siRNA in A549 cells overexpressing Sema4D. Protein levels of Sema4D, total Akt and p-Akt were examined by Western blotting. Cell proliferation, migration and invasion abilities were measured by MTT assay and Transwell assay respectively. Results showed that Sema4D siRNA significantly suppressed phosphorylation of AKT in A549 cells, but it did not alter total AKT expression. In addition, efficient down-regulation of SemaD significantly inhibit cell proliferation (P<0.05), migration (P<0.05) and invasion (P<0.05) in A549 cells. These findings suggest that Sema4D might serve as a reliable tool for early prediction of NSCLC poor prognosis. Sema4D could play an important role in promoting tumor proliferation, migration and metastasis in the NSCLC, by influencing the Akt protein phosphorylation. Inhibition of Sema4D may be a useful approach for the treatment of NSCLC.
Aged ; Antigens, CD ; biosynthesis ; Carcinoma, Non-Small-Cell Lung ; metabolism ; mortality ; pathology ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Disease-Free Survival ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms ; metabolism ; mortality ; pathology ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Invasiveness ; Phosphorylation ; Proto-Oncogene Proteins c-akt ; metabolism ; Semaphorins ; biosynthesis ; Survival Rate

Thrombocytosis and coagulation systems activation are commonly associated with disease progression and are suggested poor prognostic factors in patients with malignancies. This study aimed to investigate the prevalence and prognostic significance of thrombocytosis and elevated fibrinogen levels in patients with advanced non-small cell lung cancer (NSCLC). Initial platelet counts and fibrinogen levels were reviewed in 854 patients with histologically proven NSCLC. Thrombocytosis was defined as platelet counts > 450 x 10(9)/L. A serum fibrinogen level > 4.5 g/L was considered high. At the time of diagnosis, initial platelet counts and serum fibrinogen levels were evaluated before treatment. Clinicopathologic data including histological type, tumor, node, metastasis (TNM) stage, performance status, treatment method, and survival time were evaluated. Initial thrombocytosis was found in 6.9% of patients, and elevated fibrinogen levels were found in 55.1% of patients. Patients with thrombocytosis had a significantly poorer prognosis than patients with normal platelet counts (P < 0.001). In multivariate survival analysis, thrombocytosis was an independent prognostic factor (P < 0.001). An elevated serum fibrinogen level was associated with poor prognosis (P < 0.001). In conclusion, initial thrombocytosis and a high fibrinogen level are independent factors for predicting poor prognosis in patients with advanced NSCLC.
Aged ; Blood Platelets/*cytology ; Carcinoma, Non-Small-Cell Lung/*diagnosis/mortality/pathology ; Female ; Fibrinogen/*analysis ; Humans ; Lung Neoplasms/*diagnosis/mortality/pathology ; Male ; Middle Aged ; Neoplasm Staging ; Platelet Count ; Prognosis ; Retrospective Studies ; Survival Rate ; Thrombocytosis/complications/diagnosis