Survival Rate Of Non-small Cell Lung Cancer Patients Research Articles

An Update on the Treatment Strategy for Non-Small Cell Lung Cancer: A Current Scenario and Future Perspective

Abstract: Non-small cell lung cancer (NSCLC) is a ubiquitous form of lung cancer. Most patients already have metastasis at the time of diagnosis. Chemotherapy and radiotherapy are widely used to treat the early stages of NSCLC, but cancer relapses are common, and the mortality rate is also high. Hence, there is a definite need for newer and advanced therapies to control the recurrence and metastasis of NSCLC. Many clinical trials are underway, which could improve the current treatment options. Targeted therapy and immunotherapies are increasingly developing to expand the overall survival rate of NSCLC patients. Yet, the continuous mutation in the tumor site, drug resistance, adverse effects, and tumor recurrence pose several challenges to the efficacy of the treatment. Many drugs in phase I and II clinical trials prove significant effectiveness against NSCLC mutations. Combination therapy has shown enhanced progression-free and overall survival rates when compared to monotherapy. Recently, FDA-approved genetically engineered patients’ immune cells and chimeric antigen receptors (CAR) improved T-cells for the treatment of malignancies. This review emphasizes the recent development in the treatment regimen and strategy used for improving the outcomes of NSCLC.

Personalized adjuvant chemotherapy for stage II–III non-small cell lung cancer

Surgery is the standard of care for non-small cell lung cancer (NSCLC). The overall survival rates especially in patients with locally advanced lung cancer are low. The resistance of cancer cells to chemotherapeutic drugs reduces the efficacy of treatment. Special attention is paid to the feasibility of assessing the tumor sensitivity to certain chemotherapy drugs. Currently, the most studied predictors are monoresistance and multidrug resistance genes, such as ABCC5, RRM1, ERCC1, BRCA1, TOP1, TOP2a, TUBB3 and TYMS.The aim of the study was to analyze the outcomes of combined modality treatment using radical surgery and personalized adjuvant chemotherapy for stage II–III NSCLC.Material and Methods. The study included 120 patients with stage II–III NSCLC, who underwent radical lung resection with mediastinal ipsilateral lymph node dissection. The patients were then divided into two groups. The main group consisted of 60 patients who received personalized platinum-based adjuvant chemotherapy based on the expression levels of the genes, such as ABCC5, RRM1, ERCC1, BRCA1, TOP1, TOP2a, TUBB3 and TYMS. The control group consisted of 60 patients who received postoperative chemotherapy empirically.Results. In the main group, disease progression occurred in 14 out of 60 patients, three-year disease-free survival (DFS) was 76.7 % (the median was not reached). In the control group, DFS was 53.3 % (28 out of 60 patients), the median was 31.0 (4–36 months); the differences were statistically significant: Logrank test χ2 =4.382 p=0.036. The overall three–year survival rate was 90.0 % in the main group (6/60 patients died) and 61.7 % in the control group (23/60 patients died), the differences were statistically signifcant: Logrank test χ2 =6.915, p=0.009.Conclusion. The personalized adjuvant chemotherapy resulted in the improved three-year relapse-free and overall survival rates in NSCLC patients.

The influence of anti-cancer therapies on lymphocyte subpopulations of lung cancer patients.

There are limited data on the influence of different anti-cancer therapies on lymphocyte subpopulations and their relationships to survival of non-small cell lung cancer (NSCLC) patients. This study aimed to assess the effect of immunotherapy, chemotherapy, immunochemotherapy, adjuvant chemotherapy after surgery, and antibodies against Vascular Endothelial Growth Factors (VEGF) on B cell, T cell, and NK cell subpopulations, and the survival time of NSCLC patients. A total of 32 consecutive NSCLC patients were recruited at Pulmonology Clinic, Leipzig from January 2018 to March 2020 and enrolled in this study. Immunophenotyping was done using a FACS Canto II flow cytometer (BD Biosciences) before the administration of the planned therapy and during therapy with up to 7 observational windows for each patient targeting 130 immunologic parameters. Absolute transitional B cells was significantly increased after immunotherapy (p = 0.032), immunochemotherapy (p = 0.030), and antibodies against VEGF (p = 0.024). Similarly, absolute counts and percentage of B cells were significantly increased after adjuvant chemotherapy (p = 0.023). However, absolute counts and percentage of transitional B cells are significantly decreased after chemotherapy (p = 0.001). Activated cytotoxic T cells were significantly increased after immunotherapy (p = 0.031) and immunochemotherapy (p = 0.030). The overall survival rate of NSCLC patients was 31%. In conclusion, this study suggests that different types of anti-cancer therapies affect lymphocyte subpopulations of NSCLC patients. Further large-scale and multicentre studies are required to confirm our results and to evaluate the prognostic value of lymphocyte subpopulations.

LINC00638 promotes the progression of non-small cell lung cancer by regulating the miR-541-3p/IRS1/PI3K/Akt axis

BackgroundPreceding works reveal the function of long non-coding RNAs (abbreviated to lncRNAs) during non-small cell lung cancer (NSCLC) evolvement. We explored the profile and biological functions of the lncRNA LINC00638 in NSCLC. MethodsReverse transcription-quantitative PCR examined LINC00638 level in NSCLC and corresponding non-tumor tissues, human normal lung epithelial cells BEAS-2B, and NSCLC cells (NCI–H460, HCC-827, A549, H1299, H1975, H460). The gain- and loss-of-function assay of LINC00638 ascertained its function in modulating the proliferation, apoptosis, and invasion of NSCLC cells (HCC-827 and H460). Bioinformatics analysis investigated the underlying mechanisms. Dual luciferase reporter gene and RNA immunoprecipitation (RIP) checked the interactions between LINC00638 and microRNA (miR)-541-3p, miR-541-3p and insulin receptor substrate 1 (IRS1). ResultsLINC00638 was upregulated in NSCLC tissues by contrast to the profiles found in the corresponding non-tumor normal tissues, as well as in NSCLC cells vis-à-vis BEAS-2B cells. LINC00638 upregulation pertained to the poorer survival rates of NSCLC patients. Overexpressing LINC00638 augmented NSCLC cells’ proliferation, growth, migration, and invasion but inhibited their apoptosis, while down-regulating LINC00638 led to the opposite. miR-541-3p might be an underlying target of LINC00638, which targeted IRS1, inhibited NSCLC progression, and reversed the carcinogenic effects of LINC00638. Mechanistically, LINC00638/miR-541-3p regulated the IRS1/phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Repressing IRS1/2 using its inhibitor NT157 repressed LINC00638-mediated oncogenic effects. ConclusionLINC00638 may function as an oncogene in NSCLC by modulating the miR-541-3p/IRS1/PI3K/Akt axis.

PLK1-mediated phosphorylation of β-catenin enhances its stability and transcriptional activity for extracellular matrix remodeling in metastatic NSCLC.

Rationale: β-catenin is a component for cell adhesion and a transcriptional coactivator in epithelial-mesenchymal transition (EMT). Previously we found that catalytically active PLK1 drives EMT in non-small cell lung cancer (NSCLC), upregulating extracellular matrix factors including TSG6, laminin γ2, and CD44. To understand the underlying mechanism and clinical significance of PLK1 and β-catenin in NSCLC, their relationship and function in metastatic regulation were investigated. Methods: The clinical relevance between the survival rate of NSCLC patients and the expression of PLK1 and β-catenin was analyzed by a KM plot. Immunoprecipitation, kinase assay, LC-MS/MS spectrometry, and site-directed mutagenesis were performed to reveal their interaction and phosphorylation. A lentiviral doxycycline-inducible system, Transwell-based 3D culture, tail-vein injection model, confocal microscopy, and chromatin immunoprecipitation assays were used to elucidate the function of phosphorylated β-catenin in the EMT of NSCLC. Results: Clinical analysis revealed that the high expression of CTNNB1/PLK1 was inversely correlated with the survival rates of 1,292 NSCLC patients, especially in metastatic NSCLC. In TGF-β-induced or active PLK1-driven EMT, β-catenin, PLK1, TSG6, laminin γ2, and CD44 were concurrently upregulated. β-catenin is a binding partner of PLK1 in TGF-β-induced EMT and is phosphorylated at S311. Phosphomimetic β-catenin promotes cell motility, invasiveness of NSCLC cells, and metastasis in a tail-vein injection mouse model. Its upregulated stability by phosphorylation enhances transcriptional activity through nuclear translocation for the expression of laminin γ2, CD44, and c-Jun, therefore enhancing PLK1 expression by AP-1. Conclusions: Our findings provide evidence for the critical role of the PLK1/β-catenin/AP-1 axis in metastatic NSCLC, implying that β-catenin and PLK1 may serve as a molecular target and prognostic indicator of the therapeutic response in metastatic NSCLC patients.

EP16.03-006 Genetic Characteristics of EGFR Concurrent Variants with RB1 and TP53 in NCSLC Patients

EGFR-TKIs (tyrosine kinase inhibitor) can effectively improve the survival rate of NSCLC patients with EGFR sensitive mutations. However, concomitant alterations along with EGFR mutations often affect the effect of EGFR-TKIs. The genome characteristic of EGFR co-mutation is of great significance for guiding clinical treatment. In this study, we first reported the genetic characteristics of EGFR/RB1/TP53 co-variation in the Chinese non-small cell lung cancer (NSCLC) cohort.

PAK4 expression is associated with the prognosis in non-small cell lung cancer.

This study attempted to determine the expression of p21-activated kinase 4 (PAK4) in non-small cell lung cancer (NSCLC) tissues and the normal lung tissues. The correlation between PAK4 expression and prognosis of NSCLC patients was also evaluated in the present study. The expression level of PAK4 was measured by high-performance liquid chromatography method. Chi-square test was adopted to explore the relationship of PAK4 expression and clinical features. Kaplan-Meier survival curves were plotted to delineate the overall survival rate of NSCLC patients. Cox regression analysis was performed to evaluate the prognostic significance of PAK4 expression in NSCLC. The PAK4 expression in NSCLC tissue samples was significantly higher than that in normal lung tissues (P<0.001) and shared significant correlation with Eastern Cooperative Oncology Group score, histological type, and distant metastasis (P<0.05). Survival curve revealed that NSCLC patients with high PAK4 expression had relatively higher mortality than those with low PAK4 expression (P = .001). Cox regression analysis explained that PAK4 expression was associated with the prognosis of NSCLC patients (P = .024; HR, 3.104; 95% CI, 1.164–8.278). In a word, PAK4 was highly expressed in NSCLC tissues and could act as a prognostic factor for NSCLC patients.

Prognostic Evaluation of CT Imaging Big Data-Assisted Arterial Chemoembolization Combined with 125I Seed Implantation for Non-Small-Cell Lung Cancer.

Objective To investigate the prognostic impact of computed tomography (CT) imaging big data-assisted arterial chemoembolization combined with iodine 125 (125I) seed implantation on patients with non-small-cell lung cancer (NSCLC). Methods A total of 116 patients with intermediate and advanced NSCLC hospitalized in our hospital from August 2019 to August 2020 were selected and divided into a control group and an experiment group (58 cases in each group) by random number table method for the study. The patients in the experiment group were treated with CT imaging big data-assisted arterial chemoembolization combined with 125I seed implantation, while the patients in the control group were treated with arterial chemoembolization alone, with the use of gemcitabine combined with cisplatin (GP) in chemotherapy. The prognostic impact was determined by analyzing recent efficacy; the incidence of adverse effects; tumor size and CT perfusion parameters including blood volume (BV), blood flow (BF), and permeability surface (PS); frailty state and quality of life; and the levels of serum tumor markers including carcinoembryonic antigen (CEA), glycoconjugate antigen 125 (CA125), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), microRNA- (miRNA-) 137, and miR-379-5p. In addition, frailty status was evaluated using the Fried frailty phenotype (FP) scale, and quality of life was determined according to Karnofsky Performance Status (KPS) score. Kaplan-Meyer (KM) method was used to analyze the survival rate of NSCLC patients after a 12-month follow-up. Results The remission rate in the experiment group (77.59%) was higher than that in the control group (56.90%) (P < 0.05). Tumor size, BV, BF, PS, serum CEA and CA125 levels, and FP value in both groups were dramatically reduced after treatment compared with before treatment, especially in the experiment group after 1 and 3 months of treatment (P < 0.05). Meanwhile, the serum miR-137 and miR-379-5p levels and KPS scores in both groups were higher after treatment than before treatment, especially in the experiment group after 1 and 3 months of treatment (P < 0.05). However, there was no significant difference in the incidence of nausea and vomiting, alopecia, diarrhea, myelosuppression, and hemoptysis of NSCLC patients in both groups after treatment (P > 0.05). Further, the 12-month survival rate of NSCLC patients was higher in the experiment group (84.21%) than in the control group (64.29%) (P < 0.05). Conclusion CT imaging big data-assisted arterial chemoembolization combined with 125I seed implantation for NSCLC can improve recent efficacy and the prognosis of NSCLC patients by inhibiting tumor progression with a certain degree of safety.

M6A regulator expression patterns predict the immune microenvironment and prognosis of non-small cell lung cancer.

The m6A methylation modification is one of the most common mRNA modifications, and involved in a variety of biological processes, such as cell death, cancer stem cell formation and tumorigenesis. Increasing evidences have demonstrated that the expression patterns of m6A regulators are significantly correlated with PD-L1 level some solid tumors, but few study has explored the function of m6A regulators in the immune microenvironment and prognosis in non-small cell lung cancer (NSCLC). Survival analysis was independently conducted for 20 m6A regulators to explore their prognostic value in NSCLC, and then the prognostic risk model based on m6A regulator expression profiles is built to stratify NSCLC patients. Also, the correlation analysis between immune infiltrating cells and m6A regulators is used to reveal the impact of m6A on immune microenvironment of NSCLC. Furthermore, to explore the function of m6A as biomarker of anit-PD-L1 therapeutic effect, we explored the associations of tumor mutation burden (TMB) and PD-L1 levels to 20 m6A regulator expression patterns in NSCLC. First, the expressions of 20 m6A regulators in NSCLC tissues were significantly increased compared to normal tissues. Survival analysis revealed that three genes, METTL3, HNRNPC and VIRMA, were markedly correlated to the prognosis of NSCLC patients. In particular, cox regression analysis verified that METTL3 could be used as an independent prognostic factor to predict the survival rate of NSCLC patients. Second, the risk prognostic model built on seven m6A regulators can effectively stratify NSCLC patients, and the low-risk subgroup had better prognosis compared to high-risk group. Finally, a few m6A regulators showed significant associations with immune microenvironment, as well as TMB and PD-L1 level, suggesting that the m6A RNA methylation is indicative of therapeutic effect of anti-PD-L1 treatment. Our study identified some m6A regulatory factors as independent risk factors for the prognosis of NSCLC, and the expression patterns of m6A regulators are also correlated to the immune infiltration, as well as TMB and PD-L1 level in NSCLC. The m6A regulators could be used as biomarkers indicative of immunotherapy to NSCLC patients.

MARK2/4 promotes Warburg effect and cell growth in non-small cell lung carcinoma through the AMPKα1/mTOR/HIF-1α signaling pathway

MARKs kinase belongs to an AMPK-related family kinase plays a critical role in tumor progression, but its exact role and contribution of four different isoforms remain largely ambiguous. In this study, we used a clinical dataset compiled by The Cancer Genome Atlas (TCGA) and GEO revealed that MARK2 and MARK4 expressions were significantly upregulated in non-small cell lung cancer (NSCLC) compared with normal tissues. Furthermore, expressions of MARK2/4 were highly appeared in advanced stages and associated with the low survival rate of NSCLC patients. Functional assays demonstrated that MARK2/4 deletion or MARKs inhibition significantly suppressed aerobic glycolysis and cell growth in NSCLC cells. Mechanistically, MARK2/4 stimulates the mTOR/HIF-1α pathway and subsequently alleviates AMPK activity via physically associate with Raptor and AMPKα1, thereby facilitating aerobic glycolysis and cell growth in NSCLC cells. However, these effects were markedly reversed by MARKs inhibitor 39621, or MARK2/4 deletion, mTOR inhibitor rapamycin, or AMPK activator AICAR. Together, the data demonstrated that MARK2/4 exerts its oncogenic effects by facilitating metabolic reprogramming in NSCLC cells. Therefore, MARK2/4 might be a potential therapeutic target for lung cancer.

TMEM100 negatively regulated by microRNA‑106b facilitates cellular apoptosis by suppressing survivin expression in NSCLC.

Non‑small cell lung cancer (NSCLC) is a common malignant tumour. Nevertheless, the 5‑year survival rate of NSCLC patients remains poor. Thus, identifying critical factors involved in regulating the progression of NSCLC is important for providing potential treatment targets. In the present study, it was observed that transmembrane protein 100 (TMEM100) was significantly downregulated in NSCLC tissues compared with paired peritumoral tissues. Decreased TMEM100 expression was associated with poor clinical outcomes in NSCLC patients. Moreover, TMEM100 overexpression inhibited colony formation and facilitated apoptosis by suppressing survivin expression in NSCLC cells, whereas TMEM100 knockdown had the opposite effect. In addition, microRNA (miR)‑106b, a miR with controversial roles in different human cancers, was upregulated in NSCLC and directly downregulated TMEM100 expression. The roles of miR‑106b in cell survival were mitigated by the restoration of TMEM100. The aforementioned results indicated that TMEM100 induced cell apoptosis and inhibited cell survival by serving as a tumour suppressor and that miR‑106b‑mitigatedTMEM100 expression defined a potentially oncogenic pathway in NSCLC.

CircAGFG1 sponges miR-28-5p to promote non-small-cell lung cancer progression through modulating HIF-1α level.

Circular RNAs (circRNAs) have gained much attention for their crucial regulatory roles in human diseases and cancers. However, the role and the mechanism of circRNA ArfGAP with FG repeats 1 (circAGFG1) in non-small-cell lung cancer (NSCLC) are still largely unknown. circAGFG1 was highly expressed in NSCLC, and high expression of circAGFG1 was closely related to the low survival rate of NSCLC patients. circAGFG1 knockdown inhibited the proliferation, migration, and invasion and promoted the apoptosis of NSCLC cells. circAGFG1 bound to miR-28-5p in NSCLC cells, and circAGFG1 promoted NSCLC progression partly through sponging miR-28-5p in vitro. HIF-1α was a target of miR-28-5p, and miR-28-5p overexpression-mediated influences in NSCLC cells were partly overturned by the addition of HIF-1α overexpression plasmid. circAGFG1/miR-28-5p/HIF-1α axis regulated cellular glycolytic metabolism in NSCLC cells. circAGFG1 silencing restrained the xenograft tumor growth in vivo. circAGFG1 promoted the proliferation, migration, and invasion and suppressed the apoptosis of NSCLC cells through accelerating the glycolysis via miR-28-5p/HIF-1α axis.

Tumor Suppressor miR-584-5p Inhibits Migration and Invasion in Smoking Related Non-Small Cell Lung Cancer Cells by Targeting YKT6.

Simple SummaryCigarette smoke is a major carcinogen that causes lung cancer and induces DNA methylation. DNA methylation regulates the expression of microRNA (miRNAs), which are important regulators of cancer biology. However, the association between smoking and miRNAs has not been fully elucidated in smoking-related lung carcinogenesis. In this study, we found that miR-584-5p expression was downregulated with cancer progression using a lung carcinogenesis model cell line. Moreover, we demonstrated that miR-584-5p is downregulated by the methylation of its promoter region and that it suppresses migration and invasion by targeting YKT6 in smoking-related non-small cell lung cancer (NSCLC) cells. Our results provide a better understanding of the underlying changes in miRNA expression in smoking-related lung carcinogenesis and suggest that miR-584-5p is a potential molecular biomarker for smoking-related NSCLC.Cigarette smoke (CS) affects the expression of microRNAs (miRNAs), which are important regulators of gene expression by inducing DNA methylation. However, the effects of smoking on miRNA expression have not been fully elucidated in smoking-related lung carcinogenesis. Therefore, in this study, to investigate the change of miRNA expression pattern and to identify tumor suppressor miRNAs by smoking in lung carcinogenesis, we used lung carcinogenesis model cell lines that, derived from a murine xenograft model with human bronchial epithelial cells (BEAS-2B), exposed CS or not. The microarray analysis revealed that miR-584-5p expression was downregulated with cancer progression in lung carcinogenesis model cell lines. We confirmed by pyrosequencing that the methylation level of the miR-584-5p promoter increased with cancer progression. In vitro and in vivo experiments showed that miR-584-5p suppressed migration and invasion in non-small cell lung cancer (NSCLC) cells by targeting YKT6. Furthermore, we showed that high level of YKT6 was associated with a poor survival rate in NSCLC patients with a history of smoking. These results suggest that miR-584-5p acts as a tumor suppressor and is a potential molecular biomarker for smoking-related NSCLC.

MicroRNA-let-7e in serum-derived exosomes inhibits the metastasis of non-small-cell lung cancer in a SUV39H2/LSD1/CDH1-dependent manner.

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. Accumulating research has highlighted the ability of exosome-encapsulated microRNAs (miRNAs or miRs) as potential circulating biomarkers for lung cancer. The current study aimed to evaluate the clinical significance of serum-derived exosomal miR-let-7e as a biomarker in the metastasis of NSCLC. Initially, the expression of miR-let-7e, SUV39H2, and CDH1 in human NSCLC tissues and exosomes isolated from the serum of NSCLC patients was determined by RT-qPCR, demonstrating that miR-let-7e was downregulated in NSCLC tissues and serum-derived exosomes, while SUV39H2 was upregulated in NSCLC tissues. Kaplan-Meier method revealed that both lower miR-let-7e expression and higher SUV39H2 expression were correlated with a lower survival rate of NSCLC patients. Next, SUV39H2 was predicted and validated to be a target of miR-let-7e using dual-luciferase reporter assay. NSCLC H1299 cells following ectopic expression and depletion experiments of miR-let-7e and SUV39H2 were treated with serum-derived exosomes, after which the viability, migration, and invasion of H1299 cells were detected using CCK-8 and Transwell assays. Further, in vivo experiments were conducted to elucidate the effect of exosomal miR-let-7e on tumorigenesis. Results revealed that miR-let-7e overexpression in serum-derived exosomes inhibited SUV39H2, resulting in impaired cell viability, migration, and invasion in vitro as well as delayed tumor growth in vivo. In conclusion, the key findings of the current study demonstrate that exosomal miR-let-7e from serum possesses anticarcinogenic properties against NSCLC via the SUV39H2/LSD1/CDH1 axis.

Changes in serum inflammatory factors, adiponectin, intestinal flora and immunity in patients with non-small cell lung cancer.

The aim of this study was to explore the changes in the body state of patients with non-small cell lung cancer (NSCLC), including intestinal flora, serum inflammatory factors, immunity and adiponectin. A total of 18 NSCLC patients (disease group) and 16 healthy people from the Medical Center (control group) were selected as research objects. The levels of immune molecules immunoglobulin A (IgA), IgG and IgM, and inflammatory factors interleukin-2 (IL-2), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and IL-6 were detected via enzyme-linked immunosorbent assay (ELISA). The level of adiponectin was determined using the quantitative kit. In addition, the changes in intestinal flora were analyzed. The overall survival time of NSCLC patients was significantly affected by IL-2 (p=0.0026), CRP (p=0.03), TNF-α (p=0.014) and IL-6 (p=0.00018). It can be seen that these inflammatory factors may play important roles in the progression of NSCLC. The levels of TNF-α (p=0.037), IL-2 (p=0.043) and CRP (p=0.000) in the peripheral blood serum were significantly higher in disease group than control group. Meanwhile, the levels of IgA (p=0.040) and IgG (p=0.000) in the peripheral blood serum were significantly higher in disease group than control group. However, no significant difference was observed in the level of IgM between the two groups (p>0.05). The expression of adiponectin gene (ADIPOQ) could remarkably affect the overall survival rate of NSCLC patients, and patients with high expression of ADIPOQ exerted significantly better prognosis (p=0.017). The level of serum adiponectin was evidently higher in control group than that in disease group (p<0.05). According to the linear discriminant analysis (LDA) score of the intestinal flora in both groups, the abundance of some intestinal flora (Enterobacter and Lachnospiraceae) was markedly higher in disease group than control group (p<0.05). However, the abundance of Bifidobacteria, Pediococcus and Lactobacillus was remarkably higher in control group than disease group (p<0.05). Correlation analysis indicated that Lactobacillus was positively correlated with Bifidobacteria (r=0.44, p=0.000), whereas was negatively correlated with Enterobacter (r=-0.22, p=0.024). Furthermore, Enterobacter was negatively associated with Bifidobacteria (r=-0.15, p=0.038) and Streptococcus (r=-0.12, p=0.046). Serum inflammatory factors, adiponectin, intestinal flora and immunity may play important roles in the development of NSCLC.

Analysis of the expression levels and clinical value of miR‑365 and miR‑25 in serum of patients with non‑small cell lung cancer

The present study aimed to investigate the expression levels and clinical value of miR-365 and miR-25 in serum of patients with non-small cell lung cancer (NSCLC). Patients (180) diagnosed with NSCLC at the Affiliated Hospital of Guangdong Medical University from July 2011 to December 2013 were used as the experimental group. Volunteers (90) undergoing health examinations were used as the control group. The serum of the patients was collected after fasting in the morning. The expression levels of miR-365 and miR-25 in the serum of patients was assessed by quantitative real-time PCR (qRT-PCR), and the relationship among miR-365, miR-25 and the postoperative survival rate of NSCLC patients was analyzed. The relative expression level of miR-25 of patients with peripheral infiltration was significantly higher than that of patients without peripheral infiltration (P<0.05). There were significant differences in the relative expression level of miR-25 in different pathological grades and TNM stages, as well as with lymph node metastasis (P<0.05). The survival rate of NSCLC patients with high expression of miR-25 was significantly lower than that of NSCLC patients with low expression of miR-25 (P<0.05). The relative expression level of miR-365 of patients with peripheral infiltration was significantly lower than that of patients without peripheral infiltration (P<0.05). There were significant differences in the relative expression level of miR-365 in different pathological grades and TNM stages, as well as with lymph node metastasis (P<0.05). The survival rate of NSCLC patients with high expression of miR-365 was significantly higher than that of NSCLC patients with low expression of miR-365 (P<0.05). In conclusion, the expression levels of miR-25 and miR-365 were different in the serum of NSCLC patients, and they were closely related to certain clinical characteristics such as peripheral infiltration, pathological grade, tumor diameter, TNM stage and lymph node metastasis. Moreover, it was revealed that miR-25 and miR-365 affected the 5-year survival rate of patients. miR-25 and miR-365 could be used as important tumor markers to evaluate the prognosis of NSCLC patients.

Clinical significance of circ-MTHFD2 in diagnosis, pathological staging and prognosis of NSCLC.

To explore the clinical significance of circ-MTHFD2 in the diagnosis, pathological staging, and prognosis of non-small cell lung cancer (NSCLC). A total of 100 pairs of cancer tissues and adjacent tissues were surgically removed from NSCLC patients treated from July 2011 to January 2013 in our hospital were selected. All tissue samples were pathologically confirmed. Real Time-Polymerase Chain Reaction (qRT-PCR) was adopted to detect the expression of circ-MTHFD2 in NSCLC samples and its characteristic as a circular ribonucleic acid (circRNA). The receiver operating characteristic (ROC) curve was drawn to determine the diagnostic potential of circ-MTHFD2 in NSCLC. The relationship between circ-MTHFD2 expression and the clinical characteristics of NSCLC patients was analyzed by the χ2-test. Kaplan-Meier survival curves were depicted to assess the prognostic potential of circ-MTHFD2 in NSCLC. The effect of circ-MTHFD2 on the overall survival rate of NSCLC patients was uncovered by introducing the Cox proportional hazards model. The expression of circ-MTHFD2 in cancer tissues of NSCLC patients was higher than that in adjacent tissues (p<0.05), and there was no remarkable difference in the expression of circ-MTHFD2 before and after RNase R digestion (p>0.05). The area under the curve (AUC) of circ-MTHFD2 ROC was 0.701, with the cut-off value of 3.534, 90% sensitivity and 71% specificity. Circ-MTHFD2 expression was closely associated with smoking history, tumor size, tumor-node-metastasis (TNM) stage, lymph node metastasis, and recurrence in NSCLC patients (p<0.05). The prognosis of NSCLC patients with high expression of circ-MTHFD2 was evidently poorer than those with low expression. High expression of circ-MTHFD2 was an independent risk factor affecting the prognosis in NSCLC (p<0.05). The high expression of circ-MTHFD2 has clinical significance in the diagnosis, pathological staging, and prognosis of NSCLC.

CircEPSTI1 Promotes the Progression of Non-Small Cell Lung Cancer Through miR-145/HMGB3 Axis.

BackgroundThe high expression of circular RNA circEPSTI1 (hsa_circRNA_000479) has been reported to be associated with the malignant potential of ovarian cancer cells and triple-negative breast cancer cells. However, the expression profile and function of circEPSTI1 in non-small cell lung cancer (NSCLC) are not fully addressed.MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) was applied to measure the RNA expression of circEPSTI1, relevant microRNAs (miRNAs) and high mobility group box 3 (HMGB3) in NSCLC tissues and cells. Cell counting kit 8 (CCK8) assay, colony formation and transwell assays were conducted to detect the capacities of proliferation, colony formation and metastasis in NSCLC cells. Western blot assay was performed to detect the expression of metastasis-associated proteins and HMGB3. Animal experiment was carried out to confirm the function of circEPSTI1 in vivo. The combination between miR-145 and circEPSTI1 or HMGB3 was verified by dual-luciferase reporter assay, RNA pull-down and RIP assays.ResultsCircEPSTI1 was abnormally up-regulated in NSCLC tissues and cells in comparison with that in normal tissues and cells. The high expression of circEPSTI1 was associated with the low survival rate of NSCLC patients. CircEPSTI1 accelerated the proliferation, colony formation and motility of NSCLC cells in vitro. CircEPSTI1 silencing restrained the NSCLC tumor growth in vivo. miR-145 was validated as a target of circEPSTI1 in NSCLC cells. HMGB3 was a direct downstream target of miR-145 in NSCLC cells. The decreased abilities of proliferation, colony formation and metastasis caused by the silencing of circEPSTI1 were reversed by the depletion of miR-145 or the accumulation of HMGB3 in NSCLC cells.ConclusionCircEPSTI1 aggravated the progression of NSCLC through elevating the expression of HMGB3 via sponging miR-145.

Long Non-Coding RNA DUXAP8 Facilitates Cell Viability, Migration, and Glycolysis in Non-Small-Cell Lung Cancer via Regulating HK2 and LDHA by Inhibition of miR-409-3p.

PurposeLong non-coding RNAs (lncRNAs) were confirmed to play important roles in human cancers. In this study, we explored the functional role of lncRNA double homeobox A pseudogene 8 (DUXAP8) in non-small-cell lung cancer (NSCLC).MethodsReal-time quantitative PCR (RT-qPCR) was used to detect DUXAP8 and microRNA-409-3p (miR-409-3p) expression. CCK-8, cell colony formation assay, and Transwell migration assay were performed to measure cell growth and migration, respectively. The expression of the relative proteins was detected by Western blot. Cell glycolysis was determined by glucose uptake, adenosine triphosphate (ATP) concentration, lactate generation, extracellular acidification rate and oxygen consumption rate assays. Bioinformatics analysis and dual-luciferase reporter assay were used to measure the interaction among DUXAP8, miR-409-3p, hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA). In vivo, subcutaneous tumor formation assay was performed in the nude mice.ResultsDUXAP8 was highly expressed in NSCLC, while miR-409-3p was downregulated. High expression of DUXAP8 was positively related to the grade division and negatively associated with the 5-year survival rate of NSCLC patients. Downregulated DUXAP8 significantly suppressed cell growth, metastasis and glycolysis. Besides, DUXAP8 sponged miR-409-3p to promote HK2 and LDHA expression. DUXAP8 promoted cell viability, migration and glycolysis by regulating miR-409-3p/HK2/LDHA axis. Moreover, DUXAP8 downregulation markedly inhibited tumor growth in vivo.ConclusionOur findings demonstrated that DUXAP8 served as an oncogene in the progression of NSCLC.

An Artificial Intelligence Model for Predicting 1-Year Survival of Bone Metastases in Non-Small-Cell Lung Cancer Patients Based on XGBoost Algorithm.

Non-small-cell lung cancer (NSCLC) patients often develop bone metastases (BM), and the overall survival for these patients is usually perishing. However, a model with high accuracy for predicting the survival of NSCLC with BM is still lacking. Here, we aimed to establish a model based on artificial intelligence for predicting the 1-year survival rate of NSCLC with BM by using extreme gradient boosting (XGBoost), a large-scale machine learning algorithm. We selected NSCLC patients with BM between 2010 and 2015 from the Surveillance, Epidemiology, and End Results database. In total, 5973 cases were enrolled and divided into the training (n = 4183) and validation (n = 1790) sets. XGBoost, random forest, support vector machine, and logistic algorithms were used to generate predictive models. Receiver operating characteristic curves were used to evaluate and compare the predictive performance of each model. The parameters including tumor size, age, race, sex, primary site, histological subtype, grade, laterality, T stage, N stage, surgery, radiotherapy, chemotherapy, distant metastases to other sites (lung, brain, and liver), and marital status were selected to construct all predictive models. The XGBoost model had a better performance in both training and validation sets as compared with other models in terms of accuracy. Our data suggested that the XGBoost model is the most precise and personalized tool for predicting the 1-year survival rate for NSCLC patients with BM. This model can help the clinicians to design more rational and effective therapeutic strategies.