Prognostic Biomarker For Non-small Cell Lung Cancer Patients Research Articles

Prognostic Impact of Tissue Inhibitor of Metalloproteinase-1 in Non- Small Cell Lung Cancer: Systematic Review and Meta-Analysis.

Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) is a multifunctional natural matrixin inhibitor that is generally considered a negative regulator of cancer metastasis. Clinical studies reporting the prognostic value of TIMP-1 in Non-small Cell Lung Cancer (NSCLC) are inconsistent. Therefore, the present study aimed to determine the prognostic impact of TIMP-1 expression in NSCLC. Appropriate studies with full-text articles were identified in searches of the China National Knowledge Infrastructure (CNKI), Cochrane Library, PubMed, and Web of Science databases up to March 7, 2018. The pooled Hazard Ratio (HR) of overall survival with a 95% confidence interval (95% CI) was employed to assess the relationship between the expression of TIMP-1 and NSCLC patient survival. The meta-analysis comprised 40 studies including 3,194 patients. Study outcomes indicated that high TIMP-1 expression is independently associated with poor overall survival (HR: 1.60; 95% CI: 1.50, 1.69; P < 0.00001) with 61% of heterogeneity. In addition, we analyzed subgroups, including ethnicities, histological types, percentage of TIMP-1 expression levels, specimens, and tumor stage. All results were statistically significant. The outcome of our meta-analysis indicates that high expression levels of TIMP-1 are correlated with poor prognosis in patients with NSCLC. Expression levels of TIMP-1 represent a potential prognostic biomarker in NSCLC patients in addition to being a possible therapeutic target.

Upregulation of LINC00504 is associated with aggressive progression and poor prognosis in non-small cell lung cancer.

Long noncoding RNA LINC00504 (LINC00504) has been demonstrated to be dysregulated in several tumors. However, its function in tumor progression remains largely unclear. The goal of our present study was to determine the expressions of LINC00504 in non-small cell lung cancer (NSCLC) and its clinical associations. The expressions of LINC00504 were detected in 181 pairs of NSCLC specimens and adjacent normal tissues using qRT-PCR assays. Chi-square tests were applied to analyze the associations of LINC00504 expressions with various clinicopathological parameters of NSCLC specimens. The possible associations between LINC00504 expressions and overall survival were investigated using Kaplan-Meier assays. Univariate and multivariate assays were performed to further determine the prognostic value of LINC00504 levels in NSCLC patients. We showed that LINC00504 expressions were distinctly decreased in clinical NSCLC specimens compared to adjacent non-tumor specimens (p < 0.01). High LINC00504 expressions were strongly associated with TNM stage (p = 0.038) and lymph node status (p = 0.010). In addition, Kaplan-Meier analysis indicated that NSCLC patients with high LINC00504 expression tend to have shorter overall survival (p = 0.0036). More importantly, the results of multivariate analysis indicated LINC00504 as an independent prognostic marker (p = 0.0028). These findings revealed that LINC00504 might act as a prognostic biomarker for NSCLC patients.

MiR-486 as an unfavorable prognostic biomarker for patients with non-small cell lung cancer.

BackgroundNon-small cell lung cancer (NSCLC) is the most common malignant tumor in China. miR-486 was found to be associated with many tumors. In previous study, we aimed to investigate the expression and prognostic value of miR-486 in patients with NSCLC.MethodsIn order to measure the expression of miR-486 in 140 NSCLC patients, in situ hybridization (ISH) was made. The staining of miR-486 was scored by two independent investigators. Then, the prognostic value of miR-486 was evaluated by plotting Kaplan-Meier survival curves and making multivariate analysis.ResultsmiR-486 was mainly expressed in the cytoplasm of tumor cells. miR-486 expression was corrected with tumor differentiation (P=0.011) but not with any other clinicopathological characteristics. However, high expression of miR-486 was significantly correlated with shortened overall survival (OS) in NSCLC patients (P=0.001), especially in stage I patients (P=0.005). Multivariate analysis revealed that miR-486 was an independent prognostic factor in NSCLC patients (P=0.002).ConclusionsmiR-486 high expression predicts poor survival in patients with NSCLC. miR-486 could be used as an unfavorable prognostic biomarker for NSCLC patients.

1923P - Prognostic value of CTCs in advanced NSCLC patients treated with platinum-based chemotherapy

BackgroundLung cancer is the leading cause of cancer-related mortality worldwide. At diagnosis, 70% of patients present advanced disease being chemotherapy the standard of care. Although, specific tumour biomarkers that allow a better treatment selection and monitoring is absent at the moment. Enumeration and characterization of circulating tumor cells (CTCs) have the potential to perform as a prognostic biomarker for a precision medicine approach to lung cancer care. The present study was conducted to validate the characterization CTCs from patients with advanced Non-small cell lung cancer (NSCLC) as a valuable tool for anticipating the disease evolution and the therapy response. Methods78 patients with advanced NSCLC were enrolled in the study at HGUV and CHUS. EpCAM positive CTCs from these patients were isolated and analysed using both CellSearch technology and a qRT-PCR based approach at different times: at baseline and before the 2nd and 5th cycle treatment. A panel of genes with a relevant role for NSCLC aggressiveness and the resistance to platinum-based treatments were analysed. ResultsFrom all patients included in the study 46% were positive for CTCs using CellSearch system at baseline, showing only 12% of patients ≥5 CTCs. Additionally, patients with ≥5 CTCs showed poor PFS (4.66 vs 7.12 months, p=0.040) and OS (3,9 vs 13.43 months, p<0.001) rates compared with those patients with <5CTCs. In addition, patients with high CTCs levels during treatment also had a more aggressive disease evolution in terms of PFS and OS (p=0.007 and p=0.001, respectively). From the analyzed gene panel, patients with lower CHOKα expression at baseline had increased PFS (7.03 vs. 3.9 months, p=0.009) and OS (11.4 vs. 4.07 months, p=0.001). Furthermore, we found low CHOK α levels as a powerful marker to discriminate patients with a good response to chemotherapy from those that progressed during treatment administration (14.35 vs 5.07 months, respectively, p=0.011). ConclusionsWe demonstrated that quantification and gene expression characterization of CTCs represents an adequate strategy to identify prognostic biomarkers in NSCLC patients Supported by RTC-2014-1532-1 from MINECO and CB16/12/00350-CB16/12/00328 from CIBERONC. Legal entity responsible for the studyFIHGUV. FundingSupported from RTC-2014-1532-1 (Spanish Ministry of Economy, Industry and Competitiveness) and CB16/12/00350 and CB16/12/00328 from CIBERONC. DisclosureAll authors have declared no conflicts of interest.

Down-regulation of miR-5702 is associated with clinical progression and poor prognosis in patients with non-small-cell lung cancer.

Significant down-regulation of miR-5702 and its tumor-suppressive roles in non-small-cell lung cancer (NSCLC) have been reported previously. However, its clinical significance in NSCLC has not yet been reported. In this study, we aimed to identify the prognostic value of miR-5702 in NSCLC patients. The expression levels of miR-5702 were detected by Real-time quantitative polymerase chain reaction (RT-qPCR). The chi-square test was used for the examination of relationship between miR-5702 expression and clinicopathologic factors. The association between miR-5702 expression and overall survival in patients with NSCLC was statistically analyzed by Kaplan-Meier. Finally, univariate and multivariate models were conducted to determine the prognostic value of miR-5702 in NSCLC patients. MiR-5702 expression was lowly expressed in NSCLC tissue specimens compared with adjacent nontumor tissue (p < 0.01). It was observed that low expression of miR-5702 was associated with clinical stages (p = 0.029), lymph node metastasis (p = 0.016) and distant metastasis (p = 0.004). Moreover, Kaplan-Meier assay showed that patients with lower miR-5702 expression had worse overall survival time than that with higher miR-5702 expression (p = 0.0097). Finally, multivariate analysis showed that low expression of miR-5702 was independently associated with overall survival of NSCLC patients (HR = 3.128; 95 % CI: 1.237-5.668, p = 0.005). Our data, for the first time, indicated that miR-5702 expression may be considered as a prognostic biomarker in NSCLC patients.

Clinicopathologic Features and Prognostic Implications of Golgi Phosphoprotein 3 in Non-small Cell Lung Cancer: A Meta-analysis.

Background: A number of studies have investigated the role of Golgi phosphoprotein-3 (GOLPH3) in the pathogenesis and progression of non-small cell lung cancer (NSCLC). However, the results of previous studies are heterogeneous and controversial. The aim of this meta-analysis was to clarify its association with the clinicopathological characteristics of patients and evaluate the prognostic significance of GOLPH3 in NSCLC.Methods: A systematic search was conducted through PMC, PubMed, Medline, Web of Science, Chinese National Knowledge Infrastructure and Wanfang database. The odds ratio (OR) and hazard ratio (HR) with 95 % CI were calculated by STATA 12.0.Results: 8 qualified studies with a total of 1001 patients with NSCLC were included. Pooled results showed that GOLPH3 was highly expressed in tumor tissues compared with adjacent lung tissues (OR, 7.55), and overexpression of GOLPH3 was significantly correlated with advanced clinical stage (OR, 3.42), poor differentiation of tumor (OR, 1.97) and positive lymph node metastasis (OR, 2.58), but no association with histological type, gender, age or tumor size was found in NSCLC patients. In addition, the pooled HR for overall survival was 1.79 by univariate analysis and 1.91 by multivariate analysis. The pooled HR for progression-free survival was 2.50.Conclusions: GOLPH3 could be a risk factor for progression of NSCLC and might act as a potential prognostic biomarker for NSCLC patients.

Prognostic value of pretreatment prognostic nutritional index in non-small cell lung cancer: A systematic review and meta-analysis.

The pretreatment prognostic nutritional index has been considered a potential prognostic biomarker in patients with non-small cell lung cancer (NSCLC), but this remains controversial. Therefore, we performed a meta-analysis to systematically assess the prognostic value of the prognostic nutritional index in patients with NSCLC. We systematically searched PubMed, EMBASE, Web of Science, and CNKI. The hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) were used to evaluate the link between the prognostic nutritional index and the oncological outcomes of patients with NSCLC, including overall survival, disease-free survival/recurrence-free survival, and progression-free survival. Fifteen studies were included in this meta-analysis. Twelve of these studies explored the association between the prognostic nutritional index and the overall survival of patients with NSCLC. Our pooled analysis indicated that a low prognostic nutritional index was significantly related to adverse overall survival (HR 1.61; 95% CI 1.44, 1.81; P < 0.001). Our results also showed that the prognostic nutritional index was a negative predictor for disease-free survival/recurrence-free survival, and progression-free survival in patients with NSCLC. Our meta-analysis demonstrated that there was a close association between the prognostic nutritional index value and prognosis in NSCLC patients and that the prognostic nutritional index may act as a useful prognostic biomarker in NSCLC patients.

High UDG and BRCA1 expression is associated with adverse outcome in patients with pemetrexed treated non-small cell lung Cancer

ObjectiveThe antifolate chemotherapy agent pemetrexed has been widely used to treat non-small-cell-lung-cancer (NSCLC), but there is no clinically validated biomarker to select patients likely to respond. The aim of this study was to assess two proteins involved in DNA repair mechanisms, uracil DNA glycosylase (UDG) and BRCA1 as potential prognostic biomarkers in NSCLC patients treated with pemetrexed-based chemotherapy. Material and methodsFormalin-fixed-paraffin-embedded tumor specimens from 119 patients with advanced NSCLC treated with pemetrexed between 2004 and 2011 were retrospectively analyzed. Expression of UDG, BRCA1, and known prognostic factors ALK, TTF-1, thymidylate synthase and folylpolyglutamate synthase was assessed by immunohistochemistry using H-SCORE (product of percent stained cells and intensity of expression). Progression-free (PFS) and overall survival (OS) served as reference endpoint. ResultsMost NSCLC tumor samples had UDG positivity in at least 5% of tumor cells and 34% samples had more than 50% positive tumor cells. Using the median expression value as threshold, high UDG expression (H-SCORE≥75) was significantly associated with shorter median PFS (3-year PFS 7% vs. 37%, p = 0.045) and a trend for shorter OS (3-year OS 15% vs 42%, p = 0.066) compared to patients with low UDG. In multivariable Cox analysis, the association between high UDG and shorter PFS was close to statistically significant (p = 0.08) at a significance level of 0.05 after controlling for age, gender, ALK- and TTF1-status with hazard ratio of 2.1. Grouping patients according to combined UDG and BRCA1 expression, patients with a profile of UDGhigh/BRCA1high had the shortest PFS and OS compared to all other patient groups (p = 0.007 and 0.02, respectively). ConclusionOur results demonstrate an important prognostic role for high UDG expression in pemetrexed-treated NSCLC patients, in addition to its previously reported role in pemetrexed cytotoxicity. High UDG expression was predictive of shorter PFS and OS, and patients with a combined profile of UDGhigh/BRCA1high had the poorest outcome following pemetrexed treatment.

Baseline circulating myeloid-derived suppressor cells and response to PD-1 inhibitor in non-small cell lung cancer patients.

145 Background: Inhibitors of immune checkpoint PD-1/PD-L1 (ICI) have become a care standard in non-small cell lung cancer (NSCLC). Despite promising results, some patients cannot take advantage of immunotherapy effects. Nowadays, neither predictive nor prognostic circulating biomarkers have been found in order to select patients or to predict response to ICI. Myeloid-derived suppressor cells (MDSC) are potent immunity suppressors and may represent both a potential prognostic and a predictive biomarker. Methods: Peripheral blood samples regarding 54NSCLC patients treated with nivolumab and 5 healthy donors were prospectively included. Early-MDSC: e-MDSC (LIN-/CD14-/CD15-/HLA-DR-/CD33+), monocytic-MDSC: M-MDSC (HLA-DR low/-/CD14+/CD15-/CD11b+), polymorphonuclear-MDSC: PMN-MDSC (HLA-DR low/-/CD14-/CD15+/CD11b+) were analyzed through flow cytometry. MDSC percentage was calculated from viable peripheral blood mononuclear cells. We assessed if e-MDSC,M-MDSC and PMN-MDSC levels detected before anti-PD-1 therapy correlate with both progression-free survival (PFS) and overall survival (OS). Results: 54 patients were prospectively included: 41 with adenocarcinoma and 13 with squamous NSCLC. When compared to healthy donors, patients had significantly higher levels of circulating e-MDSC(median (range): 0.13% (0-10.9) vs0.02%(0.01-0.14), p = 0.04) and M-MDSC (median (range): 4.55% (0.08-24.18) vs1.36% (0.77-3.76), p = 0.01). Cox proportional hazard regression analysis showed that high level of M-MDSC before anti-PD-1 therapy was associated with OS (HR [CI95%]: 1.08 [1.01; 1.15],p = 0.02) and PFS (HR [CI95%]: 1.07 [1.01;1.14], p = 0.02). No prognostic impact was observed regarding e-MDSC and PMN-MDSC. Conclusions: Our study suggests that a baseline circulating high level of M-MDSC is associated with poor survival. M-MDSC may be a predictive and prognostic biomarker in NSCLC patients treated with anti-PD1. Further studies have been scheduled, including MDSC monitoring during anti-PD1 treatment, in order to confirm our findings. These data would be interesting for the development of combined therapy, targeting the suppressive environment, with ICI.

Prognostic significance of nuclear factor of activated T-cells 5 expression in non–small cell lung cancer patients who underwent surgical resection

BackgroundNuclear factor of activated T-cells 5 (NFAT5) is known to be correlated with migration or invasion of tumor cells based on previous in vitro studies. The aim of this study was to analyze the relationship between NFAT5 expression and clinical prognosis in non–small cell lung cancer (NSCLC) patients who underwent surgical resection. Materials and methodsA total of 92 NSCLC patients who underwent surgical resection were enrolled. The tissue microarray core was obtained from surgically resected tumor specimens. NFAT5 expression was evaluated by immunohistochemistry. Relationships of NFAT5 expression with disease recurrence, overall survival, and disease-free survival (DFS) were analyzed. ResultsThe mean age of 92 patients was 63.7 y. The median follow-up duration was 63.3 mo. Fifty-one (55%) patients exhibited positive expression of NFAT5. Disease recurrence in the NFAT5-positive group was significantly (P = 0.022) higher than that in the NFAT5-negative group. NFAT5-positive expression (odds ratio: 2.632, 95% confidence interval: 1.071-6.465, P = 0.035) and pathologic N stage (N1-2 versus N0; odds ratio: 3.174, 95% confidence interval: 1.241-8.123, P = 0.016) were independent and significant risk factors for disease recurrence. DFS of the NFAT5-positive group was significantly worse than that of the NFAT5-negative group (89.7 versus 48.7 mo, P = 0.011). A multivariate analysis identified NFAT5 expression (P < 0.029) as a significant independent risk factor for DFS of patients with postoperative pathologic T and N stages (P < 0.001 and P = 0.017, respectively). ConclusionsNFAT5 expression is a useful prognostic biomarker for NSCLC patients who underwent surgical resection.

Circulating microRNA-34 family low expression correlates with poor prognosis in patients with non-small cell lung cancer

To evaluate the association of plasma miR-34a/b/c expressions with the clinicopathological properties and the prognosis in non-small cell lung cancer (NSCLC) patients. A total of 196 NSCLC patients were recruited in the study. Plasma sample and tumor tissue sample were collected. Total RNA was extracted from plasma and tissue samples, and microR-34a/b/c expression was evaluated by real-time polymerase chain reaction (PCR). MiR-34a and miR-34c in plasma were positively associated with that in tumor tissue (P<0.001 and P=0.001, respectively). Plasma miR-34a expression was negatively correlated with lymph node metastasis (P=0.002), also tissue miR-34a expression was negatively associated with lymph node metastasis (P=0.018). Furthermore, plasma miR-34a high expression was correlated with prolonged disease-free survival (DFS) (P=0.011) and overall survival (OS) (P=0.011) compared to low expression, and plasma miR-34c high expression could predict longer DFS (P=0.038) than low expression, while no correlation of plasma miR-34b with DFS and OS was discovered. In terms of tissue sample, worse DFS was associated with miR-34a (P=0.002) and miR-34c (P=0.032) low expressions compared with high expressions, and miR-34a (P<0.001), as well as miR-34c (P=0.003) high expressions were associated with longer OS than low expressions. Plasma miR-34a was correlated with prolonged DFS and OS in univariate Cox model, while it could not independently predict DFS and OS of NSCLC patients in multivariate Cox model. In conclusion, circulating miR-34a and miR-34c might be served as novel prognostic biomarkers in NSCLC patients.

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.

Protein tyrosine phosphatase PTPRB regulates Src phosphorylation and tumour progression in NSCLC.

Protein tyrosine-phosphatases (PTPs) play important roles in various biological processes. Deregulation in PTP function has been implicated in carcinogenesis and tumour progression in many cancer types. However, the role of protein tyrosine phosphatase receptor type B (PTPRB) in non-small-cell lung cancer (NSCLC) tumorigenesis has not been investigated. Lentiviral vector expressing PTPRB cDNA or shRNA was infected into A549 and H1299 cell lines, followed by cell proliferation, colony formation, soft agar and invasion assays. A549 xenograft mouse model was used to evaluate in vivo function of PTPRB. Quantitative polymerase chain reaction (PCR) was used to measure PTPRB expression in NSCLC patient samples. Kaplan Meier analysis was performed to assess association between PTPRB expression and patient overall survival (OS). Multivariate analysis was performed to evaluate prognostic significance of PTPRB. Overexpression of PTPRB reduced cell proliferation rate, colony formation efficiency, soft agar growth and cell invasion in A549 and H1299 cells, as well as tumour growth rate in A549 xenograft. Knockdown of PTPRB increased Src phosphorylation and cell invasion, which was reversed by Src inhibitor PP2. Additionally, PTPRB was down-regulated in NSCLC patient and was associated with patient OS. PTPRB regulates Src phosphorylation and tumorigenesis in NSCLC. PTPRB may serve as an independent prognostic biomarker for NSCLC patients.

CHIP involves in non-small cell lung cancer prognosis through VEGF pathway.

CHIP (c-terminal Hsp70-interacting protein) is an E3 ligase playing vital roles in various cancers. The VEGF pathway has become an important therapeutic target in non-small cell lung cancer (NSCLC). However, little is known about the role of CHIP and the relationship between CHIP and VEGF-VEGFR2 (VEGF receptor 2) pathway in NSCLC. In this study we aimed to investigate the clinical function of CHIP in NSCLC and explore the relevant regulatory mechanism. QRT-PCR was performed to detect CHIP expression in NSCLC tissues. The association of CHIP expression and clinical parameters was analyzed using the Chi-square test. Kaplan- Meier and Cox analyses were performed to identify the role of CHIP in the prognosis of NSCLC patients. ELISA test was used to detect the VEGF secretion of NSCLC cells and western blot were used to detected the protein expression of VEGFR2 in NSCLC cells. and the results revealed that CHIP expression was decreased in NSCLC tissues and significantly correlated with clinical stages, lymph node metastasis and distant metastasis (P<0.05). Moreover, Kaplan-Meier and Cox regression analyses showed that patients with negative expression of CHIP had a shorter survival time and CHIP could be an independent prognostic biomarker. In addition, ELISA tests showed that CHIP negatively regulated the secretion level of VEGF. Furthermore, western blot assay indicated that the VEGFR2 protein level was reduced after CHIP over-expression. Taken together, our findings demonstrate for the first time that CHIP may serve as a promising prognostic biomarker for NSCLC patients and it may be involved in NSCLC angiogenesis through regulating VEGF secretion and expression of VEGFR2.

Prognostic significance of miR-23b in combination with P-gp, MRP and LRP/MVP expression in non-small cell lung cancer.

Recently, miR-23b has emerged as a promising new cancer biomarker but its role in lung cancer has not been established yet. Patients still do not respond well to available treatments, probably due to expression of multidrug resistance (MDR) proteins, such as P-gp, MRP and LRP/MVP. The aim of this study was to determine the role of miR-23b in non-small cell lung cancer (NSCLC) and its relationship to the patient outcome together with MDR transporter proteins. We immunohistochemically evaluated expression of P-gp, MRP and LRP/MVP and quantified the relative levels of miR-23b in 62 NSCLC patients´ samples. The prognostic significance of miR-23b and MDR proteins was tested by Kaplan-Meier and Cox-regression analysis. Our results showed that miR-23b is mostly downregulated in NSCLC samples (57/62) and that its upregulation in tumors is connected with longer progression-free survival (PFS; P = 0.065) and overall survival (OS; P = 0.048). The Cox proportional hazard model revealed that the risk of death or relapse in NSCLC patients with miR-23b downregulation increases together with LRP/MVP expression and both risks decrease with miR-23b upregulation (HRPFS = 4.342, PPFS = 0.022; HROS = 4.408, POS = 0.015). Our findings indicate that miR-23b, especially in combination with LRP/MVP expression, might serve as a suitable prognostic biomarker for NSCLC patients.

The clinical significance of FSCN1 in non-small cell lung cancer.

Fascin actin-bundling protein 1 (FSCN1) plays significant roles in biological processes such as tumor cell invasion and metastasis. However, little is known about prognostic value of FSCN1 in non-small cell lung cancer (NSCLC). FSCN1 mRNA and protein expression were detected by real-time PCR and Western blot in NSCLC tissues and paired adjacent normal lung tissues. Furthermore, the association of FSCN1 protein expression with clinicopathological characteristics including the survival was explored in 156 NSCLC patients. In our results, FSCN1 mRNA and protein expression were obviously higher in NSCLC tissues than in normal lung tissues. High levels of FSCN1 protein were positively correlated with status of differentiated degree, clinical stage, N classification, and M classification in NSCLC. Meanwhile, higher FSCN1 protein expression was significantly associated with poor overall survival in patients with NSCLC. Multivariate analyses showed that increased FSCN1 protein expression was a poor independent prognostic biomarker for NSCLC patients. In conclusions, FSCN1 plays an important role on NSCLC progression and prognosis and may serve as a convictive prognostic biomarker for NSCLC patients.

Tyrosine-protein phosphatase non-receptor type 12 expression is a good prognostic factor in resectable non-small cell lung cancer.

Tyrosine-protein phosphatase non-receptor type 12 (PTPN12) has been considered to be a tumor suppressor in human cancer, but its clinical and prognostic significance in non-small cell lung cancer (NSCLC) has not been well elucidated.A retrospective analysis of 215 patients with surgically resected NSCLCs from Sun Yat-Sen University Cancer Center between April 2002 and March 2005 was performed using immunohistochemistry and Western Blot to analyze PTPN12 expression. The association between PTPN12 expression and patient survival was investigated.Western Blots showed that the expression level of PTPN12 were higher in normal paracancerous lung tissues than in NSCLC tissues. High PTPN12 expression was less common in the presence than in the absence of visceral pleural invasion (p=0.038). Patients with PTPN12-high tumors had a longer disease-free survival (DFS) (P<0.001) and overall survival (OS) (p<0.001), especially for those with non-squamous cell carcinoma (non-SCC) (DFS, p<0.001; OS, p<0.001). Multivariate analysis confirmed that PTPN12 positivity was associated with increased survival duration (DFS, p<0.001; OS, p<0.001), independent of prognostic indicator.High PTPN12 expressive levels are associated with favorable survival duration in patients with NSCLC, especially those with non-SCC. Our study suggests that PTPN12 expression is a valuable prognostic biomarker for NSCLC patients.

Increased expression of SOX4 is a biomarker for malignant status and poor prognosis in patients with non-small cell lung cancer.

The aim of the present study was to analyze the expression of sex-determining region Y-related high mobility group box 4 (SOX4) in non-small cell lung cancer (NSCLC) and its correlation with clinicopathologic characteristics, including the survival of NSCLC patients. To observe initially the expression status of SOX4 in lung squamous cell carcinoma and adenocarcinoma at gene expression omnibus. The expression of SOX4 mRNA and protein was examined in NSCLC tissues and normal lung tissues through real-time PCR and immunohistochemistry. Meanwhile, the relationship of SOX4 expression levels with clinical characteristics of 168 NSCLC patients was analyzed by immunohistochemistry. Univariate and multivariate analyses were performed to determine the association between SOX4 expression and prognosis of NSCLC patients. In our results, SOX4 expression was increased in NSCLC tissues compared with paired normal lung tissues in microarray data (GSE3268). SOX4 mRNA and protein expression were markedly higher in NSCLC tissues than in normal lung tissues (P=0.001 and P=0.001, respectively). Using immunohistochemistry, high levels of SOX4 protein were positively correlated with status of differentiated degree (high vs. middle, P=0.004; high vs. low, P<0.001), clinical stage (I-II vs. III-IV, P<0.001), T classification (T1-T2 vs. T3-T4, P=0.004), N classification (N0-N1 vs. N2-N3, P=0.002), and M classification (M0 vs. M1, P=0.011) in NSCLC. Moreover, the higher level of SOX4 expression was markedly correlated with poor overall survival in NSCLC patients (P<0.001). Multivariate analysis suggested that increased SOX4 expression was a poor independent prognostic predictor for NSCLC patients (P=0.002). In conclusion, SOX4 plays an important role on NSCLC progression and prognosis and may serve as a convictive prognostic biomarker for NSCLC patients.

Serum miR-499 as a novel diagnostic and prognostic biomarker in non-small cell lung cancer

The aim of the present study was to determine whether serum miR-499 may be used as a biomarker for early detection of non-small cell lung cancer (NSCLC). The present study was designed as an initial screening phase and a subsequent validation phase. In the screening phase, we analyzed serum levels of miR-499 in a subset of 40 patients with stage I (n=20) and stage IV (n=20) NSCLC. In the validation phase, miR-499 expression levels in serum (n=514) and tissue (n=136) from NSCLC patients were detected in a large and independent cohort of 514 patients. miR-499 in the screening phase was found to be significantly elevated in the serum of stage I NSCLC patients compared with that in stage IV NSCLC patients (P<0.001). Validation analysis showed that serum miR-499 levels were robust in differentiating NSCLC patients from control subjects [area under the curve (AUC)=0.906; 95% confidence interval (CI)=0.879 to 0.929). Serum miR-499 levels were significantly lower in stage III and IV patients compared with those with stage I (both P<0.001) or II (both P<0.001). Low serum miR-499 levels were associated with shorter overall survival and served as an independent prognostic biomarker in NSCLC patients [hazard ratio (HR)=1.63; 95% CI=1.33-2.0; P<0.0001). In addition, low serum levels of miR-499 indicated a poor disease-free survival in stage I-II NSCLC patients. Serum miR-499 may prove to be a promising biomarker for early detection and prognosis prediction of NSCLC.

O1-027 - Minichromosome Maintenance Protein 7 Plays Essential Roles in Cancer Cell Growth and is a Potential Therapeutic Target in Human Cancer

ABSTRACT Background The research emphasis in anti-cancer drug discovery has always been to search for a drug with the greatest antitumor potential but fewest side-effects. This can only be achieved if the drug used is against a specific target located in the tumor cells. In this study, we evaluated Minichromosome Maintenance Protein 7 (MCM7) as a novel therapeutic target in cancer. Results Immunohistochemical analysis showed that MCM7 was positively stained in 196 of 331 non-small-cell lung cancer (NSCLC), 21 of 29 bladder tumor and 25 of 70 liver tumor cases whereas no significant staining was observed in various normal tissues. We also found an elevated expression of MCM7 to be associated with poor prognosis for patients with NSCLC. qRT-PCR revealed a higher expression of MCM7 in clinical bladder cancer tissues than in corresponding non-neoplastic tissues, and we confirmed that a wide range of cancers also overexpressed MCM7 by cDNA microarray analysis. Suppression of MCM7 using specific siRNAs inhibited incorporation of BrdU in lung and bladder cancer cells overexpressing MCM7, and suppressed the growth of those cells more efficiently than that of normal cell strains expressing lower levels of MCM7. Conclusions Since MCM7 expression was generally low in a number of normal tissues we examined, MCM7 has the characteristics of an ideal candidate for molecular targeted cancer therapy in various tumors and also as a good prognostic biomarker for NSCLC patients.