Poor Prognosis In Non-small Cell Lung Cancer Research Articles

The combination of anti-KIR monoclonal antibodies with anti-PD-1/PD-L1 monoclonal antibodies could be a critical breakthrough in overcoming tumor immune escape in NSCLC.

BackgroundThe anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) monoclonal antibody has a good effect in the treatment of non-small cell lung cancer (NSCLC), but not all PD-1/PD-L1 positive patients can get benefit from it. Compensatory expression of other immune checkpoints may be correlated with the poor efficacy of anti-PD-1/PD-L1 monoclonal antibodies. The inhibitory human leukocyte antigen (HLA)/killer cell Ig-like receptor (KIR) can effectively block the killing effect of natural killer (NK) cells on tumors. Our previous studies have confirmed that high expression of KIR was correlated with poor prognosis of NSCLC. Inhibitory KIR expression was positively correlated with the expression of PD-1.MethodsThe expressions of KIR 2D (L1, L3, L4, S4) (BC032422/ADQ31987/NP_002246/NP_036446, Abcam) and PD-1 (NAT 105, Cell marque) proteins was assessed by immunohistochemistry.ResultsThe expression of inhibitory KIR in tumor cells or tumor infiltrating lymphocytes (TILs) is associated with PD-1 expression. Among PD-1 positive patients, 76.3% were KIR 2D (L1, L3, L4, S4) positive on tumor cells, and 74.6% were KIR 2D (L1, L3, L4, S4) positive on TILs. We compared the expression of inhibitory KIR before and after treatment with nivolumab in 11 patients with NSCLC. We found that five (45.5%) patients had positive expression of inhibitory KIR in tumor tissue after being treated with anti-PD-1 monoclonal antibodies, two of whom exhibited a significant increase in expression of inhibitory KIR, and three showed no change.ConclusionsPD-1 expression was correlated with KIR 2D (L1, L3, L4, S4) on tumor cells or TILs. The resistance to anti-PD-1 monoclonal antibody treatment might be related to KIR. The inhibitory HLA/KIR could combine with the PD-1/PD-L1 signaling pathway negatively regulating NSCLC tumor immunity.

Testes-specific protease 50 as an independent risk factor for poor prognosis in patients with non-small cell lung cancer.

Testes-specific protease 50 (TSP50) is normally expressed in the testes and is overexpressed in various types of human cancers, including breast cancer, colorectal carcinoma and laryngocarcinoma. However, little has been reported on the association between TSP50 and non-small cell lung cancer (NSCLC). The present study aimed to detect TSP50 expression in 198 strict follow-up cases of paired NSCLC and 15 cases of normal lung parenchymal specimens using immunohistochemical staining. The expression levels of TSP50 were then correlated with the clinicopathological factors of NSCLC to assess its potential diagnostic and prognostic value. The relationship between TSP50 expression and the clinicopathological parameters of NSCLC was evaluated using χ2 and Fisher's exact tests. Survival rates for the overall population (n=198) were calculated using the Kaplan-Meier method, and univariate and multivariate analyses were performed using the Cox's proportional hazards regression model. P<0.05 was considered to indicate a statistically significant difference. The expression of TSP50 was significantly increased in NSCLC tissue compared with in adjacent non-tumor or normal lung parenchymal tissue (P<0.001). A significant association was revealed between high expression levels of TSP50 and clinicopathological characteristics including tumor differentiation (P=0.012), late tumor status (P=0.004) and late tumor node metastasis stage (P=0.026), as well as a reduced disease free survival (P=0.009) and overall survival rate (P=0.002) in all patients with NSCLC. Multivariate analyses demonstrated that high TSP50 expression in tumor tissues was significantly associated with a shorter disease-free survival rate [hazard ratio (HR) =1.590, 95% confidence interval (CI): 1.035-2.441], and with a shorter overall survival rate (HR=1.814; 95% CI: 1.156-2.846). In conclusion, the present data demonstrated that increased TSP50 protein expression may be a potential predictor of early recurrence and poor prognosis in NSCLC, and that TSP50 expression levels possess the potential to be used as a biomarker and therapeutic target for the treatment of patients with NSCLC.

High expression of CIP2A protein is associated with tumor aggressiveness in stage I-III NSCLC and correlates with poor prognosis.

The aim of this work was to examine the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A) in non-small cell lung cancer (NSCLC) and analyze its correlation with clinical outcomes. CIP2A protein levels were detected by immunohistochemistry (IHC). One hundred and eighty-four of 209 (88.3%) primary stage I–III NSCLC specimens and 4 of 38 (10.5%) adjacent normal lung tissue specimens expressed CIP2A protein. High expression of CIP2A was detected in 38.8% (81/209) of the NSCLC specimens. Patients diagnosed histologically with late-stage NSCLC (p<0.001) and malignant nodes (p=0.001) exhibited high CIP2A expression. Univariate analysis using the log-rank test identified CIP2A expression as a prognostic predictor for overall survival (p=0.005). In multivariate analyses using the Cox regression test, CIP2A expression, T stage, N stage, histological type, and chemotherapy were identified as independent prognostic factors (p=0.007, 0.001, 0.003, <0.001, and <0.001, respectively). Furthermore, Kaplan–Meier survival curves demonstrated that high CIP2A expression indicated poor prognosis in the subgroup of patients with squamous cell carcinoma (p=0.008). Similar results were noted in the subgroup of patients with adenocarcinoma, but the results did not reach statistical significance (p=0.084). We also used univariate analysis and multivariate analysis to assess the prognostic factors for overall survival in the subgroup of patients who received postoperative chemotherapy. CIP2A expression was also an independent prognostic factor in NSCLC patients who received postoperative chemotherapy (p=0.009), along with histological type (p=0.001) and N stage (p=0.034). In conclusion, adding to the accumulating evidence, our research suggested that the CIP2A expression is associated with aggressiveness and correlates with poor prognosis in NSCLC. Our findings also indicated that CIP2A might be a potential therapeutic target against NSCLC.

P0071 interacts with E-cadherin in the cytoplasm so as to promote the invasion and metastasis of non-small cell lung cancer.

As a member of the p120-catenin (p120ctn) subfamily, the p0071 study in tumor is very limited. We demonstrated the clinicopathological significance of p0071 in non-small cell lung cancer (NSCLC), as well as E-cadherin. Co-immunoprecipitation was used to detect the interaction of p0071 with E-cadherin in A549 and SPC cells (E-cadherin is mainly expressed in the cytoplasm of these cells). p0071 cytoplasmic expression was knocked down by siRNA in these cells and this effect on the RhoA activity and cell invasion and migration ability were measured. p0071 overexpression in the cytoplasm of tumor cell was correlated with lymphatic metastase and poor prognosis of NSCLC. The patients with both abnormal expression of p0071 and E-cadherin (cytoplasmic expression) had a statistically significant shorter survival than the patients without both abnormal expression (P < 0.05). There is a significant correlation between cytoplasmic overexpression of p0071 and E-cadherin in NSCLC tissues. p0071 interacted with E-cadherin in the cytoplasm of A549 and SPC cell lines. Treatment with siRNA-p0071 inhibited the invasion and migration ability of NSCLC cells. Above results confirmed that p0071 interacted with E-cadherin in the cytoplasm so as to promote the invasion and metastasis of NSCLC.

Downregulation of carbonic anhydrase IV contributes to promotion of cell proliferation and is associated with poor prognosis in non-small cell lung cancer.

The present study aimed to unveil the biological role of carbonic anhydrase IV (CA IV) and its association with clinical pathological characteristics and prognostic significance in non-small cell lung cancer (NSCLC). The relative expression level of CA IV was measured by reverse transcription-quantitative polymerase chain reaction in 114 resected NSCLC tumors and matched adjacent normal tissues and NSCLC cell lines. Overexpression and cell proliferation were assessed in human NSCLC cell lines transfected with CA IV mRNA by lentivirus-mediated technology. The association of CA IV expression with clinical pathological features and overall survival in 114 cases of NSCLC patients was analyzed. It was demonstrated that CA IV expression was significantly downregulated in NSCLC tumors and six cell lines. Reduced expression of CA IV was significantly correlated with lymph node metastasis. The overall survival of NSCLC patients with low CA IV expression was significantly shorter compared with the high expression group. Overexpression of CA IV suppressed cell proliferation in A549 and NCI-H1299 cells. The results indicate that low expression of CA IV promotes cell proliferation and serves as an indicator for poor prognosis in NSCLC.

Abstract 675: The interaction between hedgehog and EMT pathway in non-small cell lung cancer and its prognostic implication

Abstract Introduction: The Hedgehog (Hh) signaling plays essential role in transcription regulation and embryonic development. In many cancers including lung cancer, it is related to carcinogenesis and poor prognosis. This signaling also mediates epithelial to mesenchymal transition (EMT) by paracrine mechanism in various diseases. We aim to study the interaction between Hedgehog and EMT pathway and its clinical implication in non-small cell lung cancer (NSCLC). Method: Total 271 cases of NSCLC who received surgical resection in Yeouido St. Mary’s Hospital between 1997 and 2011 were included. For immunohistochemical analysis of Hh and EMT related proteins, 4um sections were sliced from tissue microarray. Hh signaling proteins including Sonig hedgehog (Shh), Patched (Ptch), Smoothened (Smo), Glioma-associated oncogene (Gli-1) and Suppressor of fused (Sufu), and EMT associated molecules including E-cadherin and vimentin were analyzed. Staining intensity (IS) was estimated as follows 0 (no staining), +1 (weak), +2 (distinct), +3 (strong). Intensity score (IS) ≥1 was defined as positive. Medical record was retrospectively reviewed. The study was approved by the institutional review board the hospital. Result: The median age was 63 (18-84) years, and 65.3% were male. Squamous cell carcinoma was diagnosed in 113 (41.7%), adenocarcinoma in 153 (56.5%), and mixed type in 153 (56.5%). Stage 1 and 2 were 46.9% and 30.6%, respectively, and 8 cases had distant metastasis. The Hh proteins showed positive correlation each other. For EMT, the expressions of Hh protein was significantly correlated with tumoral and stromal positivity of vimentin, and inversely with positivity of E-cadherin (P = 0.002 and P = 0.028, respectively). The expression of Hh proteins were significantly associated with lymph node metastasis along with large tumor size (P = 0.021 and P = 0.035, respectively). In survival analysis, expressions of Shh and Gli1 were independent predictor of disease free survival and cancer-specific survival (P = 0.007 and P = 0.025, respectively). Conclusion: Expression of Hh protein is associated with epithelial-mesenchymal transition and associated with poor prognosis in NSCLC. Citation Format: Ho Jung An, Tae-Jung Kim, Young Jo Sa, Chang Suk Kang. The interaction between hedgehog and EMT pathway in non-small cell lung cancer and its prognostic implication [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 675. doi:10.1158/1538-7445.AM2017-675

TRIM59 is a novel potential prognostic biomarker in patients with non-small cell lung cancer: A research based on bioinformatics analysis.

Lung cancer is the leading cause of cancer-associated mortality worldwide and its prognosis is poor. Few effective biomarkers for non-small cell lung cancer (NSCLC) have been translated into the clinical practice aiming to assist in the treatment plan design and prognosis evaluation. The aim of the present study was to identify novel potential prognostic biomarkers for NSCLC. Tripartite motif 59 (TRIM59) was identified from a microarray dataset of matched-samples and was verified as an aberrantly upregulated gene in NSCLC tissue. The expression level of TRIM59 in NSCLC subtypes was observed to be significantly increased in large cell lung carcinoma and squamous cell carcinoma as compared with that in adenocarcinoma. Its expression correlated with several clinicopathological features, including gender, smoking habits, and unfavorable tumor node and pathological stages. Notably, TRIM59 demonstrated a negative correlation with survival time and its overexpression indicated a poor prognosis in NSCLC. Furthermore, univariate and multivariate Cox's regression analyses indicated that TRIM59 was an independent prognostic factor in tumor tissue as compared with age, gender, tumor stage, node stage, and metastasis. Gene set enrichment analysis and protein-protein interaction network construction revealed that TRIM59 was associated with oncogenic mammalian target of rapamycin (MTOR) and eukaryotic initiation factor 4E (EIF4E) signaling through ubiquitin C binding. In conclusion, it was revealed that TRIM59 is a novel prognostic biomarker modulating oncogenic MTOR and EIF4E signaling pathways in NSCLC. These findings provided a novel insight into the clinical application of TRIM59. Therefore, TRIM59 may serve as an independent predictor for prognosis and a potential therapeutic target for NSCLC.

HLA-G 14 bp insertion/deletion polymorphism is a prognostic factor for non-small-cell lung cancer

Objective To study the correlation between human leucocyte antigen-G (HLA-G) 14 bp insertion/deletion (I/D) polymorphism and susceptibility to non-small cell lung cancer (NSCLC) as well as poor prognosis in NSCLC. Methods A total of 113 patients with NSCLC and 150 age- and sex-matched healthy subjects were genotyped by PCR to analyze the HLA-G 14 bp insertion/deletion polymorphism in them. Epidermal growth factor receptor (EGFR) gene mutation in patients with NSCLC was detected by using amplification refractory mutation system (AMRS). Expression of HLA-G in NSCLC tissues was detected with immunohistochemistry. All patients with NSCLS were followed up to collect survival data, which were further analyzed with Kaplan-Meier method. Results The frequency of HLA-G 14 bp D/D genotype was significantly higher in the patients with NSCLC than that in the healthy subjects (χ2=3.907, P=0.048, OR=1.66). Among the patients with NSCLC, HLA-G 14 bp I/I genotype carriers had a shorter overall survival time as compared with that of HLA-G 14 bp I/D or HLA-G 14 bp D/D genotype carriers (P=0.005). Patients who received chemotherapy or radiation had significantly shorter survival time than those received EGFR-targeted therapy (P=0.001). Among patients who were positive for EGFR mutation, HLA-G 14 bp D/D genotype carriers had longer survival time than those carrying HLA-G 14 bp I/I or HLA-G 14 bp I/D genotype (P=0.041). The expression of HLA-G was closely correlated with HLA-G 14 bp polymorphism in patients with NSCLC (P=0.001). Conclusion These data, reported for the first time, indicates that HLA-G 14 bp polymorphism might be a genetic factor related to the susceptibility to NSCLC and associated with survival in patient with NSCLC after excluding the interference of molecular targeted agents. Key words: HLA-G; Polymorphism; Non-small-cell lung cancer; Targeted therapy

FGF2/FGFR1 regulates autophagy in FGFR1-amplified non-small cell lung cancer cells

BackgroundAutophagy is a conserved catabolic process to degrade cellular organelles. The role of autophagy in cancer development is complex. Amplification of fibroblast growth factor receptor 1 (FGFR1) is one of the most frequent targets in lung squamous cell carcinoma (SQCC). Whether fibroblast growth factor 2 (FGF2)/FGFR1 contributes to the regulation of autophagy remains elusive.MethodsAutophagic activity was evaluated by immunoblotting for microtubule-associated protein 1 light chain 3 (LC3), formation of GFP-LC3 puncta, and monodansylcadaverine (MDC) staining. The effect of autophagy inhibition on cell survival was assessed by cell viability and apoptosis assays.ResultsWe elucidated that FGFR1 activation suppressed autophagy. Pharmacological or genetic inhibition of FGFR1 by AZD4547 or FGFR1 short hairpin RNA (shRNA) induced autophagy in FGFR1-amplified non-small cell lung cancer (NSCLC) cells, H1581 and H520 cells. Mechanistic study revealed that the induction of autophagy by FGFR1 inhibition was mediated through inhibiting the ERK/MAPK pathway not by AKT pathway, accompanied by upregulation of beclin-1. Furthermore, activation of ERK/MAPK by transfection with a constitutively active MEK1 (caMEK1) construct or knockdown of beclin-1 by RNAi could attenuate autophagy induced by FGFR1 inhibition. Beclin-1 expression was inversely correlated with MEK1 phosphorylation. Inhibition of autophagy by beclin-1 silencing could enhance apoptosis after AZD4547 treatment in H1581 and H520 cells. High levels of LC3B mRNA was a marker of poor prognosis in NSCLC patients.ConclusionsSimultaneously inhibiting FGFR1 and autophagy could enhance cell death which should be further explored in vivo.

Human papillomavirus type 16 E6 oncoprotein promotes proliferation and invasion of non-small cell lung cancer cells through Toll-like receptor 3 signaling pathway.

Human papillomavirus (HPV) oncoproteins play vital roles in non-small cell lung cancer (NSCLC) pathogenesis, and Toll-like receptors (TLRs) contribute to tumor progression. However, interaction between HPV oncoproteins and TLR signaling in NSCLC progression remains unclear. Thus, the aim of the study was to explore effects of HPV16 E6 oncoprotein-induced TLRs pathway on growth and invasion of NSCLC cells and to examine potential mechanisms being involved. Recombinant plasmid (pcDNA-HPV16 E6) expressing HPV16 E6 protein was constructed. The expression prolife of TLRs was measured in NSCLC cell line A549 with or without pcDNA-HPV16 E6 transfection by real-time reverse polymerase chain reaction and Western blot. Cellular proliferation, invasion, cytokine productions, and downstream signaling pathways were also examined in TLR3-silencing/pcDNA-HPV16 E6 transfect A549 cells. Overexpression of HPV16 E6 increased proliferation, invasion, proliferation cytokine secretion, and TLR3 expression of A549 cells, while TLR3 silence inhibited HPV16 E6-induced tumor bioactivities of A549 cells. Down-regulation of TLR3 suppressed HPV16 E6-induced phosphorylation of Src, but did not affect TRIF expression. Moreover, inhibition of Src pathway also suppressed proliferation and invasion of A549 cells. In conclusion, HPV16 E6 oncoprotein promoted the bioactivities of NSCLC cells. TLR3-Src signaling pathway might be involved in this procession by up-regulation of cytokine production. The interaction between HPV16 E6 protein and TLR3 might contribute to the poor prognosis of NSCLC.

Clinicopathological significance and prognostic role of EZH2 expression in non-small cell lung cancer

ObjectiveThe aim of this study was to investigate the clinicopathological characteristics and prognostic role of enhancer of zeste homologue 2 (EZH2) expression in non-small cell lung cancer (NSCLC). MethodsThe correlation between EZH2 expression and the clinicopathological characteristics, including sex, smoking history, tumor differentiation, histologic type, tumor stage, and lymph node metastasis, was evaluated through a meta-analysis. In addition, the prognostic value of EZH2 expression was elucidated. This study included 1,932 patients with NSCLC from 11 eligible studies. ResultsThe overall rate of EZH2 expression was 0.548 [95% confidence interval (CI) 0.491–0.604]. There were significant correlations between EZH2 expression and male sex and smoking history. The expression rate of EZH2 was significantly lower in adenocarcinoma than in other histologic types. Furthermore, EZH2 expression rates were higher in NSCLC with moderately and poorly differentiation and nodal disease than in well-differentiated NSCLC without nodal disease. There was a significant correlation between EZH2 expression and worse overall and disease-free survival [hazard ratio (HR) 1.938, 95% CI 1.617–2.323 and HR 1.713, 95% CI 1.366–2.149, respectively]. Subgroup analysis revealed no significant difference for the prognostic effect of EZH2 expression between histologic types or detection methods. ConclusionOur data collectively suggest that EZH2 expression is significantly correlated with aggressive tumor behavior and poor prognosis in NSCLC.

Long non-coding RNA LUCAT1 is associated with poor prognosis in human non-small lung cancer and regulates cell proliferation via epigenetically repressing p21 and p57 expression.

Recently, long non-coding RNAs (lncRNAs) have been recognized as playing key roles in regulating cellular processes, such as proliferation, invasion, and metastasis. These lncRNAs have been shown to be abnormally expressed in tumorigenic processes. However, the role and clinical relevance of LUCAT1 in non-small-cell lung cancer (NSCLC) remain unclear. In this study, we found that the expression of LUCAT1 was significantly up-regulated in NSCLC tissues compared to non-tumor tissues, and its expression was associated with tumor size, tumor–node–metastasis (TNM) stage and overall survival (OS). Further experiments showed that LUCAT1 knockdown inhibited cell proliferation both in vitro and in vivo. Mechanistic investigations showed that LUCAT1 plays a key role in G0/G1 arrest. We further demonstrated that LUCAT1 was associated with polycomb repressor complexes (PRC2) and that this association was required for epigenetically repression of p21 and p57, thus contributing to the regulation of NSCLC cell cycle and proliferation. In summary, our results show that LUCAT1 could regulate tumorigenesis of NSCLC and be biomarker for poor prognosis in NSCLC.

PinX1 Is a Potential Prognostic Factor for Non-Small-Cell Lung Cancer and Inhibits Cell Proliferation and Migration.

PinX1 has been identified as a suppressor of telomerase enzymatic activity. However, the tumour-suppressive roles of PinX1 in different types of human cancers are unclear. PinX1 expression status and its correlation with clinicopathological features in non-small-cell lung cancer (NSCLC) have not been investigated. Accordingly, in this study, we aimed to evaluate the roles of PinX1 in NSCLC. PinX1 expression status was examined by immunohistochemistry using tissue microarray from a total of 158 patients. Correlations among PinX1 expression, clinicopathological variables, and patient survival were analysed. Furthermore, we overexpressed PinX1 in NSCLC cells and tested telomerase activity using real-time quantitative telomeric repeat amplification protocol (qTRAP) assays. Proliferation and migration of NSCLC cells were examined using the MTS method, wound healing assays, and transwell assays, respectively. Our results showed that negative PinX1 expression was associated with a poor prognosis in NSCLC. Sex, smoking status, lymph gland status, subcarinal lymph node status, pathological stage, and PinX1 expression were related to survival. PinX1 was not an independent prognostic factor in NSCLC. PinX1 overexpression inhibited proliferation and migration in NSCLC cells by suppressing telomerase activity. Our findings suggested that PinX1 could be a potential tumour suppressor in NSCLC and that loss of PinX1 promoted NSCLC progression.

The Prognostic and Clinicopathological Significance of IGF-1R in NSCLC: a Meta-Analysis

Background/Aims: Accumulating studies have reported that IGF-1R (Insulin-like growth factor-1 receptor) is aberrantly expressed in NSCLC (non-small cell lung cancer), but the role of IGF-1R in NSCLC remains controversial. The present paper assessed the precise role of IGF-1R in NSCLC. Methods: We comprehensively searched PubMed, EMBASE, and Web of Science in March 2017. Combined HRs and ORs were used to evaluate the prognostic and clinicopathological significance of IGF-1R in NSCLC respectively. Results: A total of 10 eligible studies including 8 on overall survival, and 10 on clinicopathological features were identified from the databases. The results showed that high expression of IGF-1R was associated with shorter OS (overall survival) of NSCLC patients (pooled HR 1.17,95 % CI 1.00–1.36). In addition, we found that IGF-1R was related to smoking status (OR=1.82, 95 % CI=1.35-2.44) and IGF-1R tended to be highly expressed in SCC (squamous cell carcinoma) (OR=3.40 95 % CI: 1.95-5.95). Conclusions: In summary, this meta-analysis revealed that high expression of IGF-1R was associated with poor prognosis in NSCLC.

High Serum HDGF Levels Are Predictive of Bone Metastasis and Unfavorable Prognosis in Non-Small Cell Lung Cancer.

Hepatoma-derived growth factor (HDGF) is a heparin-binding protein possessing mitogenic activity and could be secreted from necrotic cells passively or actively, thereby functioning as a damage-associated molecular pattern (DAMP). The high expression of HDGF in non-small cell lung cancer (NSCLC) tissues is associated with unfavorable prognosis. However, the clinical significance of serum HDGF has not been elucidated in NSCLC yet. In the present study, we compared the serum levels of HDGF in 235 patients with NSCLC (141 adenocarcinoma and 94 squamous cell carcinoma cases) with those in 40 healthy subjects. Moreover, we explored the correlation between serum HDGF levels and clinicopathologic factors or the overall survival rates. We thus found that the serum HDGF levels were significantly higher in NSCLC patients than those in healthy subjects (P < 0.001). Moreover, there was no significant difference in the serum HDGF levels between adenocarcinoma and squamous cell carcinoma. Importantly, the higher serum levels of HDGF were significantly associated with bone metastasis and with lower overall survival rates. Thus, serum HDGF was identified as an independent prognostic factor indicating poor prognosis of NSCLC. Using A549 human lung adenocarcinoma cell line, we demonstrated that an autophagy inhibitor, chloroquine, could inhibit the HDGF secretion, while quercetin, an autophagy inducer derived from a traditional Chinese drug, could facilitate HDGF secretion. In conclusion, high serum levels of HDGF were significantly correlated to bone metastasis and poorer prognosis of NSCLC. We suggest that anti-HDGF therapy is potential to protect NSCLC patients with advanced stages from bone metastasis.

Clinicopathological and prognostic significance of Oct-4 expression in patients with non-small cell lung cancer: a systematic review and meta-analysis.

Octamer-binding transcription factor 4 (Oct-4) has been identified to participate in the tumorigenicity and malignancy of non-small cell lung cancer (NSCLC). However, its definite prognostic roles in NSCLC still remain a debate. Therefore, we conducted this meta-analysis to evaluate the prognostic value of Oct-4 expression in NSCLC and its relationship to some major clinicopathological characteristics. A comprehensive literature retrieval was performed in PubMed, EMBASE and the Web of Science to identify the full-text articles that met our eligibility criteria. Odds ratio (OR) with 95% confidence interval (CI) severed as the summarized statistics for clinicopathological assessments, and hazard ratio (HR) with 95% CI served as the summarized statistics for prognostic assessments. Q-test and I(2)-statistic were used to evaluate the level of heterogeneity. Potential publication bias was detected by both Begg's test and Egger's test. There were 16 retried articles with 1,363 NSCLC cases included into this meta-analysis. Oct-4 expression was found to be significantly associated with the unfavorable outcomes for differentiation degree (OR: 3.065; 95% CI: 1.568-5.957; P=0.001), TNM stage (OR: 3.695; 95% CI: 2.252-6.063; P<0.001) and lymphatic metastasis (OR: 2.372; 95% CI: 1.504-3.742; P<0.001), but not associated with the histological subtypes, gender, age and smoking status. Oct-4 expression was also significantly associated with the poor prognosis of NSCLC (HR: 3.030; 95% CI: 2.283-4.021; P<0.001). The prognostic roles of Oct-4 expression in NSCLC still remained statistically reliable in the subgroups stratified by statistical analysis, patients' origins, positively-stained sites and histological subtypes. Our meta-analysis indicates that Oct-4 can serve as a strong biomarker predicting the poor clinicopathological and prognostic characteristics of NSCLC. More high-quality studies based on a large sample size will be very helpful to further validate and modify our findings in the future.

Prognostic significance of circulating laminin gamma2 for early-stage non-small-cell lung cancer.

BackgroundLaminin gamma2 (Ln-γ2) chain, a distinctive subunit of heterotrimeric laminin-332, is frequently upregulated in carcinomas and is of great importance in cell migration and invasion. Despite this, the status of circulating Ln-γ2 in lung cancer patients is still uncertain.Patients and methodsIn this retrospective study, serum samples from 538 all-stage (stages I–IV) patients with non-small-cell lung cancer (NSCLC) and 94 age-matched healthy volunteers were investigated by enzyme-linked immunosorbent assay. Data were statistically analyzed in combination with clinicopathological information.ResultsCirculating Ln-γ2 was markedly increased in NSCLC, even in stage I cases (P<0.01), reflecting the progression of lung cancer. Survival analysis on 370 eligible patients indicated that serum Ln-γ2-negative patients survived much longer compared with Ln-γ2-positive individuals (P=0.028), and it was especially the case for stage I (P<0.001), stage T1 (P=0.001), and stage N0 patients (P=0.038), all of whom represented early-stage cases. For the advanced patients, however, overall survivals were not significantly different among stages II–IV (P=0.830), stages T2–T4 (P=0.575), stages N1–N3 (P=0.669), and stage M1 (P=0.849). Cox analysis subsequently defined serum Ln-γ2 as an independent prognostic indicator of NSCLC, particularly for early-stage patients. Furthermore, we demonstrated the association of serum Ln-γ2 with smoking behavior, but its association with tumor progression and early prognostic significance were not altered in the nonsmoking cohort.ConclusionOur study demonstrated that elevation of circulating Ln-γ2 was an early-emerging event in NSCLC and was significantly associated with poor prognosis in NSCLC, especially for early-stage cases.

Clinicopathological and prognostic significance of regulatory T cells in patients with non-small cell lung cancer: A systematic review with meta-analysis.

The prognostic and clinicopathological value of regulatory T cells (Tregs) infiltration in patients with non-small cell lung cancer (NSCLC) remains undetermined. A comprehensive literature search of electronic databases (up to December 2015) was conducted. Relationship between Tregs infiltration and clinicopathological features, recurrence-free survival (RFS) and overall survival (OS) was investigated by synthesizing the qualified data. A total of 1303 NSCLC patients from 11 studies were included. The pooled hazard ratio (HR) for survival showed that high Tregs infiltration had no effect on RFS (HR = 2.03, 95% CI: 0.61–3.44, P = 0.708) and OS (HR = 1.20, 95% CI: 0.58–1.62, P = 0.981). High FoxP3+ Tregs infiltration was significantly associated with poor OS in NSCLC (HR = 3.88, 95% CI: 2.45–5.40, P = 0.000). Test methods, ethnicity and types of specimens had no effect on predicting prognosis of Tregs infiltration. While high Tregs infiltration was significantly correlated with smoking status [odds ratios (ORs) = 1.54, 95% CI: 1.15–2.08; P = 0.004], none of other clinicopathological characteristics such as gender, histological type, lymph node metastasis status, tumor size, vascular invasion, lymphatic invasion and pleural invasion were associated with Tregs infiltration. The present study demonstrated that high FoxP3+ Tregs infiltration was significantly associated with poor prognosis in NSCLC and smoking status.

Expression of miRNA-26b in the diagnosis and prognosis of patients with non-small-cell lung cancer.

To investigate the correlation between miR-26b and non-small-cell lung cancer (NSCLC). NSCLC tissues and normal lung tissues that were more than 7 cm adjacent from tumor were collected from 154 NSCLC patients. Additionally, 63 normal specimens from benign lung disease were selected as the control group. Real-time fluorescent quantitative PCR was used to detect miR-26b expression in tissues. miR-26b expression in NSCLC tissues was significantly lower than in other two types of tissues. Receiver operating characteristic curve analysis showed that the area under the curve was 0.856 with sensitivity and specificity of 79.9 and 79.4%, respectively. miR-26b expression was a risk factor for poor prognosis of NSCLC. The expression of miR-26b is downregulated in NSCLC tissues, and it might be useful in the diagnosis and prognosis of NSCLC patients.

Prognostic value of platelet to lymphocyte ratio in non-small cell lung cancer: a systematic review and meta-analysis.

The prognostic value of the platelet-to-lymphocyte ratio (PLR) in non-small cell lung cancer (NSCLC) remains controversial. We therefore conducted a meta-analysis of published studies to determine the prognostic value of PLR in NSCLC. A systematic search was performed in PubMed, Web of Science and Embase for relevant studies. The data and characteristics of each study were extracted, and the hazard ratio (HR) at a 95% confidence interval (CI) was calculated to estimate the effect. We also performed subgroup and meta-regression analyses. A total of 2,889 patients in 12 studies were enrolled in this meta-analysis, and the pooled HR of 1.492 (95% CI: 1.231–1.807, P < 0.001) indicated that patients with an elevated PLR are expected to have a shorter overall survival (OS) after treatment. This meta-analysis indicates that a high PLR might be a predictive factor of poor prognosis in NSCLC. Further large-cohort studies are needed to confirm these findings.