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

OBJECTIVEThis study was designed to investigate the correlation factors for occurrence and progression-free survival of patients with cavitating lung cancer.

METHODSWe collected the clinical data of 947 lung cancer patients. Tumor cavitation was observed in 51 patients at baseline and in 23 patients after treatment, while was not discovered in other 873 patients. Multifactor logistic regression was performed to analyze the correlation factors for occurrence. The independent predictors of PFS were analyzed with Cox proportional regression. Survival curves were constructed with the Kaplan-Meier product limit method and compared using the log-rank test.

RESULTSIn the 947 cases, the proportion of cases with baseline cavitation was 5.4% and the incidence of cavitation after treatment was 2.6%. Multivariate logistic regression analysis revealed that the occurrence of baseline cavitation is related to age, history of diabetes, history of drinking, pathologic types, tumor location, tumor diameter and distant metastasis (P < 0.05). Multifactor logistic regression analysis revealed that the occurrence of post-therapeutic cavitation is related to sex, pathologic types and tumor diameter (P < 0.05).The median PFS of patients with baseline cavitation (7.3 months) was significantly longer than the cases without it (5.2 months) (P = 0.002). While there was no significant difference between the median PFS of patients with post-therapeutic cavitation and patients without it (5.1 months vs. 5.3 months, P = 0.060). Cox proportional regression analysis revealed that cyfra21-1 is related to PFS of patients with baseline cavitaion (P < 0.05) and smoking history is related to PFS of patients with post-therapeutic cavitaion (P < 0.05).

CONCLUSIONSPatients with baseline and post-therapeutic cavitation present different clinical features and progression-free survivals. The PFS of patients with baseline cavitation is longer than that of the cases without it. On the contrary, PFS of patients with post-therapeutic cavitation is shorter than the patients without it.

Antigens, Neoplasm ; metabolism ; Disease-Free Survival ; Humans ; Kaplan-Meier Estimate ; Keratin-19 ; metabolism ; Lung Neoplasms ; mortality ; pathology ; therapy ; Regression Analysis ; Retrospective Studies ; Risk Factors ; Time Factors

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

BACKGROUNDPatients with single station mediastinal lymph node (N2) non-small cell lung cancer (NSCLC) have a better prognosis than those with multilevel N2. The molecular factors which are involved in disease progression remain largely unknown. The purpose of this study was to investigate gene expression differences between single station and multilevel N2 NSCLC and to identify the crucial molecular factors which are associated with progress and prognosis of stage N2 NSCLC.

METHODSGene expression analysis was performed using Agilent 4×44K Whole Human Genome Oligo Microarray on 10 freshfrozen lymph node tissue samples from single station N2 and paired multilevel N2 NSCLC patients. Real-time reverse transcription (RT)-PCR was used to validate the differential expression of 14 genes selected by cDNA microarray of which four were confirmed. Immunohistochemical staining for these validated genes was performed on formalin-fixed, paraffinembedded tissue samples from 130 cases of stage N2 NSCLC arranged in a high-density tissue microarray.

RESULTSWe identified a 14 gene expression signature by comparative analysis of gene expression. Expression of these genes strongly differed between single station and multilevel N2 NSCLC. Four genes (ADAM28, MUC4, CLDN1, and IGF2) correlated with the results of microarray and real-time RT-PCR analysis for the gene-expression data in samples from 56 NSCLC patients. Immunohistochemical staining for these genes in samples from 130 cases of stage N2 NSCLC demonstrated the expression of IGF2 and CLDN1 was negatively correlated with overall survival of stage N2 NSCLC.

CONCLUSIONSOur results suggest that the expression of CLDN1 and IGF2 indicate a poor prognosis in stage N2 NSCLC. Further, CLDN1 and IGF2 may provide potential targeting opportunities in future therapies.

Adult ; Aged ; Carcinoma, Non-Small-Cell Lung ; metabolism ; mortality ; pathology ; Claudin-1 ; analysis ; genetics ; Female ; Humans ; Immunohistochemistry ; Insulin-Like Growth Factor II ; analysis ; genetics ; Lung Neoplasms ; metabolism ; mortality ; pathology ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis

Lung cancer rarely occurs in young patients. Recent studies have demonstrated that epidemiologic data are closely correlated to some molecular characteristics. We investigated the clinicopathologic characteristics of lung adenocarcinoma in young patients and evaluated immunohistochemically detected epidermal growth factor receptor (EGFR) mutation status and anaplastic lymphoma kinase (ALK) positivity. Among lung adenocarcinoma patients, 31 cases were of the < or = 40 yr-old group and 261 cases of > 50 yr-old group. Young patients were more likely to be females (67.7% vs 40.2%), and nonsmokers (58.1% vs 45.2%) and more often had high TNM stage (stage IV was 80.6% vs 52.1%) and had a high rate of distant metastasis (51.6% vs 28.0%) compared with older patients. The signet ring cell feature was more common (25.8% vs 11.5%) and lepidic growth pattern was rarely present (3.2% vs 16.5%) in the adenocarcinoma of young patients. There was no significant survival difference between the two age groups. The rate of EGFR mutation status and ALK positivity did not show a statistical difference between two groups. In conclusion, lung adenocarcinoma of young patients demonstrates distinct pathologic features with frequent presence of a signet ring cell feature and rare occurrence of lepidic growth pattern. Further investigation for other genetic abnormalities would be needed.
Adenocarcinoma/metabolism/mortality/*pathology ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Female ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Lung Neoplasms/metabolism/mortality/*pathology ; Male ; Middle Aged ; Mutation ; Neoplasm Staging ; Receptor Protein-Tyrosine Kinases/metabolism ; Receptor, Epidermal Growth Factor/metabolism ; Smoking

BACKGROUND/AIMS: Oxidative stress results in protein oxidation and is implicated in carcinogenesis. Sulfiredoxin (Srx) is responsible for the enzymatic reversal of inactivated peroxiredoxin (Prx). Nuclear factor E2-related factor 2 (Nrf2) binds to antioxidant responsive elements and upregulates the expression of Srx and Prx during oxidative stress. We aimed to elucidate the biological functions and potential roles of Srx in lung cancer. METHODS: To study the roles of Srx and Prx III in lung cancer, we compared the protein levels of Nrf2, Prxs, thioredoxin, and Srx in 40 surgically resected human lung cancer tissues using immunoblot and immunohistochemical analyses. Transforming growth factor-beta1, tumor necrosis factor-alpha, and camptothecin treatment were used to examine Prx III inactivation in Mv1Lu mink lung epithelial cells and A549 lung cancer cells. RESULTS: Prx I and Prx III proteins were markedly overexpressed in lung cancer tissues. A significant increase in the oxidized form of a cysteine sulfhydryl at the catalytic site of Prxs was found in carcinogenic lung tissue compared to normal lung tissue. Densitometric analyses of immunoblot data revealed significant Srx expression, which was higher in squamous cell carcinoma tissue (60%, 12/20) than in adenocarcinoma (20%, 4/20). Also, Nrf2 was present in the nuclear compartment of cancer cells. CONCLUSIONS: Srx and Prx III proteins were markedly overexpressed in human squamous cell carcinoma, suggesting that these proteins may play a protective role against oxidative injury and compensate for the high rate of mitochondrial metabolism in lung cancer.
Adenocarcinoma/*enzymology/genetics/mortality/pathology ; Animals ; Antineoplastic Agents, Phytogenic/pharmacology ; Blotting, Western ; Camptothecin/pharmacology ; Carcinoma, Squamous Cell/*enzymology/genetics/mortality/pathology ; Cell Line, Tumor ; Humans ; Immunohistochemistry ; Lung Neoplasms/*enzymology/genetics/mortality/pathology ; Mink ; NF-E2-Related Factor 2/*metabolism ; Oxidoreductases Acting on Sulfur Group Donors/genetics/*metabolism ; Peroxiredoxin III/*metabolism ; Peroxiredoxins/metabolism ; Prognosis ; RNA Interference ; Reactive Oxygen Species/metabolism ; Transfection ; Transforming Growth Factor beta1/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Up-Regulation

The purpose of this study was to investigate risk factors of postoperative pneumonia (POP) after lung cancer surgery. The 417 lung cancer patients who underwent surgical resection in a tertiary referral hospital were included. Clinical, radiological and laboratory data were reviewed retrospectively. Male and female ratio was 267:150 (median age, 65 yr). The incidence of POP was 6.2% (26 of 417) and in-hospital mortality was 27% among those patients. By univariate analysis, age > or = 70 yr (P < 0.001), male sex (P = 0.002), ever-smoker (P < 0.001), anesthesia time > or = 4.2 hr (P = 0.043), intraoperative red blood cells (RBC) transfusion (P = 0.004), presence of postoperative complications other than pneumonia (P = 0.020), forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 70% (P = 0.002), diffusing capacity of the lung for carbon monoxide < 80% predicted (P = 0.015) and preoperative levels of serum C-reactive protein > or = 0.15 mg/dL (P = 0.001) were related with risk of POP. Multivariate analysis showed that age > or = 70 yr (OR = 3.563, P = 0.014), intraoperative RBC transfusion (OR = 4.669, P = 0.033), the presence of postoperative complications other than pneumonia (OR = 3.032, P = 0.046), and FEV1/FVC < 70% (OR = 3.898, P = 0.011) were independent risk factors of POP. In conclusion, patients with advanced age, intraoperative RBC transfusion, postoperative complications other than pneumonia and a decreased FEV1/FVC ratio have a higher risk for pneumonia after lung cancer surgery.
Adult ; Age Factors ; Aged ; Aged, 80 and over ; C-Reactive Protein/analysis ; Carbon Monoxide/metabolism ; Erythrocyte Transfusion ; Female ; Forced Expiratory Volume ; Hospital Mortality ; Humans ; Incidence ; Logistic Models ; Lung Neoplasms/pathology/*surgery ; Male ; Middle Aged ; Neoplasm Staging ; Odds Ratio ; Pneumonia/epidemiology/*etiology/mortality ; *Postoperative Complications ; Retrospective Studies ; Risk Factors ; Vital Capacity

Although continuous low-dose (metronomic [MET]) therapy exerts anti-cancer efficacy in various cancer models, the effect of long-term MET therapy for hepatocellular carcinoma (HCC) remains unknown. This study assessed the long-term efficacy of MET on suppression of tumor growth and spontaneous metastasis in a rat model of HCC induced by administration of diethylnitrosamine for 16 wk. The rats were divided into 3 groups: MTD group received intraperitoneal (i.p.) injections of 40 mg/kg cyclophosphamide on days 1, 3, and 5 of a 21-day cycle; Control and MET groups received i.p. injections of saline and 20 mg/kg cyclophosphamide twice a week, respectively. Anti-tumor and anti-angiogenic effects and anti-metastatic mechanisms including matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were evaluated. Twelve wk of MET therapy resulted in a significant reduction in intrahepatic tumors than control or MTD therapy. The MET group had fewer proliferating cell nuclear antigen-positive cells and decreased hypoxia-inducible factor-1alpha levels and microvessel density. Lung metastases were detected in 100%, 80%, and 42.9% in the control, MTD, and MET groups, respectively. MET therapy significantly decreased expression of TIMP-1, MMP-2 and -9. For mediators of pro-MMP-2 activation, MET therapy induced significant suppression in the TIMP-2 and MMP-14 level. The survival in the MET group was significantly prolonged compared to the control and MTD groups. Long-term MET scheduling suppresses tumor growth and metastasis via its potent anti-angiogenic properties and a decrease in MMPs and TIMPs activities. These results provide a rationale for long-term MET dosing in future clinical trials of HCC treatment.
Animals ; Antineoplastic Agents/*administration & dosage/*pharmacology ; Carcinoma, Hepatocellular/chemically induced/*drug therapy/mortality/pathology ; Cell Proliferation/drug effects ; Cyclophosphamide/*administration & dosage/*pharmacology ; Diethylnitrosamine ; Disease Models, Animal ; Gene Expression Regulation, Neoplastic/*drug effects ; Liver Cirrhosis/chemically induced ; Liver Neoplasms/chemically induced/*drug therapy/mortality/pathology ; Lung Neoplasms/drug therapy/pathology/secondary ; Male ; Matrix Metalloproteinases/metabolism ; Neovascularization, Pathologic/enzymology/physiopathology ; Rats ; Rats, Sprague-Dawley ; Survival Analysis ; Tissue Inhibitor of Metalloproteinases/metabolism ; Tumor Burden/drug effects

Lack of surface Fas expression is a main route for apoptotic resistance which is considered an important mechanism of tumorigenesis and tumor progression. Fas and FasL expressions in 110 non-small cell lung carcinomas (NSCLCs) were investigated to evaluate their roles in pulmonary carcinogenesis and to examine the clinicopathologic significance of Fas expression with its relationship with p53 and bcl-2 overexpressions. Immunohistochemical analysis using tissue microarray demonstrated that a large proportion of NSCLC patients (60%) showed lack of membranous Fas expression. The Fas-negative cases revealed the significantly lower survival rate than Fas-positive ones. Also, the loss of Fas receptor expression was found more frequently in advanced stage and higher nodal status. FasL protein was increased in most NSCLCs (89%) compared to normal lungs. p53 and bcl-2 overexpressions showed no association with Fas expression. Conclusively, reduced membranous Fas expression as a mechanism of apoptotic resistance is considered to play an important part of the pulmonary carcinogenesis, which may predict poor survival and have a bad prognostic influence. Increased FasL expression is thought to be a basis for the immune evasion in NSCLCs. The rare bcl-2 overexpression suggests that this anti-apoptotic protein is unlikely to play a role in the apoptotic resistance of NSCLCs.
Antigens, CD95/*metabolism ; Apoptosis ; Carcinoma, Non-Small-Cell Lung/*metabolism/mortality ; Cell Survival ; Comparative Study ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Korea/epidemiology ; Lung Neoplasms/*metabolism/mortality/pathology ; Male ; Membrane Glycoproteins/*metabolism ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; Prognosis ; Proto-Oncogene Proteins c-bcl-2/*metabolism ; Research Support, Non-U.S. Gov't ; Risk Assessment/methods ; Risk Factors ; Survival Analysis ; Survival Rate ; Tumor Markers, Biological/*metabolism ; Tumor Necrosis Factors/*metabolism ; Tumor Suppressor Protein p53/*metabolism

OBJECTIVEThis study was to clarify E-cadherin expressions in non-small cell lung cancer (NSCLC) and its correlation with patients' prognosis.

METHODSTissue microarrays (TMAs) containing specimens from 365 different NSCLC were constructed, covering all stages and almost all histological types of this disease. Slides were immunohistochemically stained with antibodies against E-cadherin. Expression pattern of the protein was analyzed with relation to the clinicopathological. Correlations of the results with patients' overall survival were also examined.

RESULTSImmunohistochemical staining revealed that E-cadherin protein was localized mainly on membranes and the cytoplasm of NSCLC tumors cells. Reduced E-cadherin expression was evident in 32.1%. Reduced E-cadherin expression significantly correlated with lymph nodes metastasis (chi(2) = 16.430, P = 0.001), histological dedifferentiation (chi(2) = 9.243, P = 0.010) and advanced clinical stage (chi(2) = 9.421, P = 0.024). There was no significant difference in E-cadherin expression between squamous cell carcinoma and adenocarcinoma. E-cadherin reduced expression correlated with a poor prognosis (P < 0.0001) in univariate analysis. Multivariate analysis showed a significantly lower survival probability for patients with reduced E-cadherin (P < 0.001), and E-cadherin was an independent prognostic factor for survival of NSCLC patients.

CONCLUSIONSIt suggests that dysfunction of E-cadherin has an important impact in the progression of lung cancer. As an independent prognostic factor, expression of E-cadherin can predict outcome of different group, together with conventional prognostic factors, and subsequently make appropriate management.

Adult ; Aged ; Aged, 80 and over ; Cadherins ; biosynthesis ; Carcinoma, Non-Small-Cell Lung ; metabolism ; mortality ; secondary ; Female ; Follow-Up Studies ; Humans ; Immunohistochemistry ; Lung Neoplasms ; metabolism ; mortality ; pathology ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Survival Rate