Prognosis Of Non-small Cell Lung Cancer Research Articles

Utilizing Bioinformatics Technology to Explore the Potential Mechanism of Danggui Buxue Decoction against NSCLC.

While lung cancer poses a serious threat to human health, non-small-cell lung cancer (NSCLC) is the most common type of lung cancer. Danggui Buxue Decoction (DBD) is a classical traditional antitumor medicine commonly used in China. However, the potential mechanism of DBD against NSCLC has not yet been expounded. Therefore, this study clarified the potential molecular mechanism and key targets of DBD in NSCLC treatment through several technological advances, such as network pharmacology, molecular docking, and bioinformatics. Firstly, the relative active ingredients and key DBD targets were analyzed, and subsequently, a drug-ingredient-target-disease network diagram was constructed for NSCLC treatment with DBD, resulting in the identification of five main active ingredients and ten core targets according to the enrichment degree. The enrichment analysis revealed that DBD can achieve the purpose of treating NSCLC through the AGE-RAGE signaling pathway in diabetic complications. Secondly, the molecular docking approach predicted that quercetin and hederagenin have the best working mechanisms with PDE3A and PTGS1, while the survival analysis results depicted that high PDE3A gene expression has a relatively poor prognosis for NSCLC patients (p < 0.05). Additionally, PDE3A is mainly distributed in the LU65 cell line that originated from Asian population. In summary, our study results showed that DBD can treat NSCLC through the synergistic correlation between multiple ingredients, multiple targets, and multiple pathways, thus effectively improving NSCLC prognosis. This study not only reflected the medicinal value of DBD but also provided a solid structural basis for future new drug developments and targeted therapies.

NCAPG is a prognostic biomarker of immune infiltration in non-small-cell lung cancer.

Purpose: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths. The protein NCAPG plays a significant role in tumor development. Patients & methods: We set up a tissue microarray (containing 140 NSCLC and ten normal lung tissues) and performed immunohistochemistry to assess NCAPG expression in the tissues of 140 patients. The prognostic value of NCAPG in NSCLC was assessed using the univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier plots. We analyzed the association between NCAPG and immune infiltration in NSCLC. Results: Multifactorial analysis and Kaplan-Meier plots revealed that upregulation of NCAPG expression was an independent factor in the prognosis of NSCLC. Data from CIBERSORT showed a negative correlation between NCAPG and the expression of memory CD4+ T cells, CD8+ T cells, dendritic cells, macrophages, mast cells and natural killer cells (p<0.001). Gene set enrichment analysis revealed that cell cycle, adhesion and proliferation were significantly enriched in samples with a high NCAPG expression. Conclusion:NCAPG is a novel biomarker of prognosis and is associated with immune cell infiltration in the tumor microenvironment. Thus it may be a potential target in NSCLC treatment.

Targeting TFAP2C/PDCD6 Pathway by lncRNA PP7080 Expedites Tumorigenesis and Contributes to an Immunosuppressive Tumor Microenvironment in Non‐Small Cell Lung Cancer

AbstractLong noncoding RNAs (lncRNAs) play essential roles in various biological processes. Nevertheless, advance exploration is warranted to elaborate the therapeutic implications and detailed mechanisms of lncRNAs in non‐small cell lung cancer (NSCLC). In the present study, lncRNA PP7080 is found highly expressed and correlated with a poorer prognosis for NSCLC. Knockout of PP7080 diminishes cell proliferation, migration, and invasion, but accelerates cell apoptosis in vitro, and impeded tumor growth in vivo. While elevated PP7080 facilitates cell proliferation, migration and invasion, repressed cell apoptosis in vitro, and accelerated xenograft tumor growth in vivo. Additionally, downregulated DNMT1 is found contributing the higher PP7080 expression via regulation of DNA methylation at PP7080 promoter‐regions in NSCLC. Furthermore, PP7080 directly bound with TFAP2C and facilitated TFAP2C phosphorylation at Ser434 site, and then upregulated PDCD6 expression through binding with its promoters. Furthermore, highly expressed PP7080/PDCD6 correlated with immune‐suppressing tumor microenvironment (TME) in NSCLC. Collectively, the results identified PP7080 mainly localized in the nucleus and functioned its oncogenic role via regulating NSCLC initiation, advancement, and contributing to an immune‐resistant TME through TFAP2C/PP7080/PDCD6 axis, implying PP7080 as a novel therapeutic target for NSCLC.

CircRNA SOD2 motivates non-small cell lungs cancer advancement with EMT via acting as microRNA-2355-5p’s competing endogenous RNA to mediate calmodulin regulated spectrin associated proteins-2

ABSTRACT Circular RNAs (circRNAs) are closely linked with human cancer development such as non-small-cell lung cancer (NSCLC). However, the characteristics and specific functions of most circRNAs in NSCLC remained unknown. Previous studies have suggested that circRNA SOD2 (CircSOD2) expression was upregulated in a number of cancers. This study aimed to explore the functions of circSOD2 in NSCLC advancement with epithelial-mesenchymal transition (EMT). Expression profile analysis of circSOD2, miR-2355-5p, and calmodulin-regulated spectrin-associated protein 2 (CAMSAP2) was detected by real-time quantitative PCR (RT-qPCR). Transwell assay, cell migration assay, CCK8, ELISA, RIP assay, RNA pull-down assay, and Western blot analysis were performed to evaluate the functions of circSOD2, miR-2355-5p, and CAMSAP2. We found elevated expression of circSOD2 and CAMSAP2 while reduced expression of miR-2355-5p in NSCLC tumor tissues. Silencing or overexpression of CircSOD2 resulted in increased or decreased expression of miR-2355-5p, respectively. Mechanically, we showed that silencing of CircSOD2 and overexpression of miR-2355-5p resulted in the reduced rate of NSCLC cell proliferation. Inhibition of miR-2355-5p reversed the changes induced via silencing of CircSOD2. MiR-2355-5p binds to the CircSOD2 promoter and triggered its stimulation, which further activated circSOD2 expression. CircSOD2 suppression impaired lung cancer cell growth, cell migration, prohibited cell cycle progression, and in vivo tumor growth by targeting miR-2355-5p expression in NSCLC tissues. Meanwhile, increased expression of CAMSAP2 reversed the changes stimulated by the elevated level of miR-2355-5p in NSCLC progression. This innovative signaling axis CircSOD2/miR-2355-5p/CAMSAP2 illustrated the new horizon to investigate NSCLC tumorigenesis and provided new prognosis and treatment of NSCLC.

Long Non-Coding RNA AL513318.2 as ceRNA Binding to hsa-miR-26a-5p Upregulates SLC6A8 Expression and Predicts Poor Prognosis in Non-Small Lung Cancer.

BackgroundStudies have demonstrated that the regulatory role of competitive endogenous RNA (ceRNA) networks is closely related to tumorigenesis, which provides new targets for tumor therapy. In this study, the focus was to explore the ceRNA networks that regulate SLC6A8 expression and their prognosis in non-small cell lung cancer (NSCLC).MethodsFirstly, the Cancer Genome Atlas (TCGA) data combined with immunohistochemical staining was used to compare SLC6A8 expression in NSCLC tissues and normal tissues. Thereafter, samples from the immunohistochemical staining of NSCLC were integrated with clinical follow-up data for prognostic analysis. The Starbase database was employed to search for SLC6A8-targeted miRNAs and lncRNAs, and survival analysis was performed using clinical data from TCGA to obtain SLC6A8 expression and prognosis-related ceRNA networks. Finally, the prognostic and therapeutic prospects of SLC6A8 in NSCLC were further analyzed from methylation sites and the immune microenvironment.ResultsThe study results revealed that SLC6A8 was significantly overexpressed in NSCLC tissues compared to normal tissues, and clinical follow-up data showed that the overexpression group was associated with poor prognosis. In addition, the Starbase data combined with TCGA clinical data analysis demonstrated that the AL513318.2/hsa-miR-26a-5p/SLC6A8 network regulates SLC6A8 overexpression in NSCLC and is associated with poor prognosis. Methylation analysis revealed that 11 methylation sites were closely associated with the prognosis of NSCLC. In addition, the immune prognostic risk model showed that the high-risk group was associated with a poorer prognosis than the low-risk group, despite showing a better immunotherapy outcome.ConclusionIn summary, the AL513318.2/hsa-miR-26a-5p/SLC6A8 network upregulates SLC6A8 expression in NSCLC and is associated with poor prognosis. Therefore it may be a prognostic biomarker of NSCLC and a potential therapeutic target.

MicroRNA-200a-3p and GATA6 are abnormally expressed in patients with non-small cell lung cancer and exhibit high clinical diagnostic efficacy.

Lung cancer is one of the main threats to human health. Survival of patients with lung cancer depends on timely detection and diagnosis. Among the genetic irregularities that control cancer development and progression, there are microRNAs (miRNAs/miRs). The present study aimed to investigate the expression patterns of miR-200a-3p and transcription factor GATA-6 (GATA6) in peripheral blood of patients with non-small cell lung cancer (NSCLC) and their clinical significance. The expression patterns of miR-200a-3p and GATA6 in the peripheral blood of patients with NSCLC and healthy subjects were measured via reverse transcription-quantitative PCR. The correlation between GATA6/miR-200a-3p expression and their diagnostic efficacy were analyzed by receiver operating characteristic curve analysis. The association between miR-200a-3p/GATA6 expression with the patient clinicopathological characteristics, and their correlation with carcinoembryonic antigen (CEA), neuron specific enolase (NSE) and squamous cell carcinoma antigen (SCCAg) were evaluated. The cumulative survival rate was examined, and whether miR-200a-3p and GATA6 expression levels were independently correlated with the prognosis of NSCLC was analyzed using multivariate logistic regression model. The results demonstrated that the expression of miR-200a-3p was high and that of GATA6 was low in the peripheral blood of patients with NSCLC, and both exhibited high clinical diagnostic efficacy. miR-200a-3p was revealed to target GATA6 by dual-luciferase assay. miR-200a-3p in the peripheral blood was correlated with TNM stage, lymph node metastasis and distal metastasis, while GATA6 in the peripheral blood was correlated with TNM stage and lymph node metastasis. miR-200a-3p and GATA6 were positively correlated with CEA and SCCAg, but not with NSE. High expression of miR-200a-3p and low expression of GATA6 predicted poor prognosis in patients with NSCLC. After adjusting for TNM stage, lymph node metastasis, distance metastasis, GATA6, CEA, NSE and SCCAg in the logistic regression model, it was indicated that the high expression of miR-200a-3p increased the risk of death in patients with NSCLC. Collectively, it was revealed that miR-200a-3p and GATA6 were abnormally expressed in the peripheral blood of patients with NSCLC. Serum levels of miR-200a-3p >1.475 and GATA6 <1.195 may assist the early diagnosis of NSCLC. GATA6 may function in NSCLC as a miR-200a-3p target, which may provide a future reference for NSCLC early diagnosis and treatment.

Prognostic Value of Glasgow Prognostic Score in Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Background: Systemic inflammation is a key factor in tumor growth. The Glasgow Prognostic Score (GPS) has a certain value in predicting the prognosis of lung cancer. However, these results still do not have a unified direction. Methods: A systematic review and meta-analysis were performed to investigate the relationship between GPS and the prognosis of patients with non-small cell lung cancer (NSCLC). We set patients as follows: GPS = 0 vs. GPS = 1 or 2, GPS = 0 vs. GPS = 1, GPS = 0 vs. GPS = 2. We collected the hazard ratio (HR) and the 95% confidence interval (CI). Results: A total of 21 studies were included, involving 7333 patients. We observed a significant correlation with GPS and poor OS in NSCLC patients (HRGPS=0 vs. GPS=1 or 2 = 1.62, 95% CI: 1.27–2.07, p ≤ .001; HRGPS=0 vs GPS=1 = 2.14, 95% CI:1.31–3.49, p ≤ .001; HRGPS=0 vs. GPS=2 = 2.64, 95% CI: 1.45–4.82, p ≤ .001). Moreover, we made a subgroup analysis of surgery and stage. The results showed that when divided into GPS = 0 group and GPS = 1 or 2 group, the effect of high GPS on OS was more obvious in surgery (HR = 1.79, 95% CI: 1.08–2.97, p = .024). When GPS was divided into two groups (GPS = 0 and GPS = 1 or 2), the III-IV stage, higher GPS is associated with poor OS (HR = 1.73, 95% CI: 1.43–2.09, p ≤ .001). In the comparison of GPS = 0 and GPS = 1 group (HR = 1.56, 95% CI: 1.05–2.31, p = .026) and the grouping of GPS = 0 and GPS = 2(HR = 2.23, 95% CI: 1.17–4.26, p = .015), we came to the same conclusion. Conclusion: For patients with NSCLC, higher GPS is associated with poor prognosis, and GPS may be a reliable prognostic indicator. The decrease of GPS after pretreatment may be an effective way to improve the prognosis of NSCLC.

Long non-coding RNA LINRIS is upregulated in non-small cell lung cancer and its silencing inhibits cell proliferation by suppressing microRNA-10a maturation

ABSTRACT Long noncoding RNA LINRIS (LINC00920) is known to participate in colorectal cancer. This study aimed to explore the role of LINRIS in non-small cell lung cancer (NSCLC). NSCLC and adjacent non-tumor tissues were collected from 62 NSCLC patients. LINRIS expression was detected using real-time quantitative PCR (RT-qPCRs). The 62 NSCLC patients were monitored every month for 5 years to evaluate the role of LINRIS in predicting the prognosis of NSCLC. The effects of LINRIS silencing on microRNA-10a (miR-10a) precursor and mature miR-10a levels were assessed by RT-qPCR. Cell proliferation was measured using Cell Counting Kit-8 (CCK-8) assays. LINRIS expression was upregulated in NSCLC tissues. High LINRIS levels predicted poor survival of NSCLC patients. LINRIS were positively correlated with mature (miR-10a) levels but not miR-10a precursor. In NSCLC cells, LINRIS silencing showed no role in miR-10a precursor accumulation but downregulated mature miR10a level. Moreover, LINRIS silencing inhibited cell proliferation, while miR-10a overexpression increased cell proliferation and inhibited the role of LINRIS silencing. Overall, LINRIS silencing may inhibit NSCLC cell proliferation by suppressing miR-10a maturation. Abbreviations: Non-small cell lung cancer (NSCLC); Reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR); LncRNA long intergenic noncoding RNA for IGF2BP2 stability (LINRIS).

Exosome-mediated miR-7-5p delivery enhances the anticancer effect of Everolimus via blocking MNK/eIF4E axis in non-small cell lung cancer

Everolimus is a kind of mammalian target of rapamycin (mTOR) inhibitors. Activated mitogen-activated protein kinase interacting kinases/eukaryotic translation initiation factor 4E (MNK/eIF4E) axis plays a crucial role in resistance to Everolimus in non-small cell lung cancer (NSCLC). The eIF4E phosphorylation increased by mTOR inhibitors is mainly mediated by MNKs. However, the mechanisms are poorly understood. Recently, extensive reprogramming of miRNA profiles has also been found after long-term mTOR inhibitor exposure. Our previous studies have confirmed that tumor suppressor miR-7-5p is decreased in A549 cells after treatment with Everolimus. Exactly, MNK1 is the target of miR-7-5p. In this study, we investigated the biological functions and potential molecular mechanisms of miR-7-5p in the NSCLC undergoing treatment with Everolimus. We confirmed that Everolimus targeted mTORC1 inducing NSCLC cells to secrete miR-7-5p-loaded exosomes in Rab27A and Rab27B-dependent manners. Loss of intracellular miR-7-5p induced phosphorylation of MNK/eIF4E axis, but a supplement of extra exosomal miR-7-5p could reverse it. Of note, both low expression of miR-7-5p and elevated MNK1 protein were associated with a poor prognosis of NSCLC. Both endogenous miR-7-5p and exo-miR-7-5p enhanced the therapeutic efficacy of Everolimus by inhibiting the proliferation, migration, and metastasis of NSCLC in vitro and in vivo. The combination of miR-7-5p with Everolimus induced apoptosis to exhibit a synergistic anticancer therapeutic efficacy through dual abrogation of MNK/eIF4E and mTOR in NSCLC. In conclusion, Everolimus decreases the intracellular miR-7-5p by releasing of miR-7-5p loaded exosomes from NSCLC cells in Rab27A and Rab27B dependent manners. Either endogenous miR-7-5p or exo-miR-7-5p combined with Everolimus can enhance the anticancer efficacy by targeting MNK/eIF4E axis and mTOR. Besides, both low levels of miR-7-5p and positive expression of MNK1 act as independent poor prognostic biomarkers for NSCLC. Therefore, restoring miR-7-5p carried by exosome may be a promising novel combined therapeutic strategy with Everolimus for NSCLC.

Identification of TIMELESS and RORA as key clock molecules of non-small cell lung cancer and the comprehensive analysis

BackgroundThe incidence rate of non-small cell lung cancer (NSCLC) has been increasing worldwide, and the correlation of circadian rhythm disruption with a raised risk of cancer and worse prognosis has been shown by accumulating evidences recently. On the other hand, drug resistance and the impact of tumor heterogeneity have been inevitable in NSCLC therapy. These both lead to an urgent need to identify more useful prognostic and predictive markers for NSCLC diagnosis and treatment, especially on the aspect of circadian clock genes.MethodsThe expression of the main clock genes in cancer was probed with TIMER and Oncomine databases. The prognostic value of key clock genes was probed systematically with the Kaplan–Meier estimate and Cox regression on samples from TCGA database. RT-qPCR was performed on patient tissue samples to further validate the results from databases. The functional enrichment analysis was performed using the “ClusterProfiler” R package, and the correlation of key clock genes with tumor mutation burden, immune checkpoint, and immune infiltration levels were also assessed using multiple algorithms including TIDE, TIMER2.0, and XCELL.ResultsTIMELESS was significantly upregulated in lung tissue of clinical lung cancer patients as well as TCGA and Oncomine databases, while RORA was downregulated. Multivariate Cox regression analysis indicated that TIMELESS (P = 0.004, HR = 1.21 [1.06, 1.38]) and RORA (P = 0.047, HR = 0.868 [0.755, 0.998]) has a significant correlation with overall survival in NSCLC. Genes related to TIMELESS were enriched in the cell cycle and immune system, and the function of RORA was mainly focused on oncogenic signaling pathways or glycosylation and protein activation. Also, TIMELESS was positively correlated with tumor mutation burden while RORA was negatively correlated with it. TIMELESS and RORA were also significantly correlated with immune checkpoint and immune infiltration levels in NSCLC. Additionally, TIMELESS showed a significant positive relationship with lipid metabolism.ConclusionsTIMELESS and RORA were identified as key clock genes in NSCLC, and were independent prognostic factors for overall survival in NSCLC. The function of them were assessed in many aspects, indicating the strong potential of the two genes to serve as biomarkers for NSCLC progression and prognosis.

Breaking the crosstalk of the Cellular Tumorigenic Network by low-dose combination therapy in lung cancer patient-derived xenografts

Non-small cell lung cancer (NSCLC) is commonly diagnosed at advanced stages limiting treatment options. Although, targeted therapy has become integral part of NSCLC treatment therapies often fail to improve patient’s prognosis. Based on previously published criteria for selecting drug combinations for overcoming resistances, NSCLC patient-derived xenograft (PDX) tumors were treated with a low dose combination of cabozantinib, afatinib, plerixafor and etoricoxib. All PDX tumors treated, including highly therapy-resistant adeno- and squamous cell carcinomas without targetable oncogenic mutations, were completely suppressed by this drug regimen, leading to an ORR of 81% and a CBR of 100%. The application and safety profile of this low dose therapy regimen was well manageable in the pre-clinical settings. Overall, this study provides evidence of a relationship between active paracrine signaling pathways of the Cellular Tumorigenic Network, which can be effectively targeted by a low-dose multimodal therapy to overcome therapy resistance and improve prognosis of NSCLC.

Detection of Mitochondrial DNA Copy Number in Plasma Exosomes of Patients with Non-small Cell Lung Cancer

For the prevalence of lung cancer and its poor diagnosis, the seeking of the efficient biomarkers for this disease is an urgent requirement, especially from non-invasive samples such as plasma. The mitochondria DNA (mtDNA) copy number change has been evaluated as a potential indicator of cancer risk, however, there have been few studies regarding mtDNA in plasma derived exosomes. In this study, the mtDNA copy number was measured on 29 plasma exosome samples of patients with non-small cell lung cancer (NSCLC) and 29 plasma exosome samples of cancer-free controls by real-time PCR assay, then being statistically analyzed to evaluate the relationship between these figures and several pathological features of NSCLC patients. As the results, the existence of mtDNA in exosomes isolated from plasma was detected through PCR assay using primers covering most of the mtDNA length. The relative mtDNA copy numbers determined in the exosomes of the disease and control groups were 1619.1 ± 2589.0 and 1207.0 ± 1550.0, respectively, whereas these values in two disease stages were 783.6 ± 759.3 (stage I-II) and 2647.0 ± 3584.0 (stage III-IV). Comparing among these groups, the difference was only statistically significant between the disease groups of stage I-II and stage III-IV (p&lt;0.05), the group of stage III-IV and the control group (p&lt;0.05). Indeed, the mtDNA copy number is associated with tumor stage and stage N (p&lt;0.05). On the other aspect, the smoking habit of NSCLC patients could be an underlying reason behind the alteration in mtDNA copy number in the plasma exosomes. In short, our study demonstrates that the mtDNA copy number in exosomes resourced from plasma could be a potential biomarker for the detection and prognosis of NSCLC.

A prognostic model of non small cell lung cancer based on TCGA and ImmPort databases

Bioinformatics methods are used to construct an immune gene prognosis assessment model for patients with non-small cell lung cancer (NSCLC), and to screen biomarkers that affect the occurrence and prognosis of NSCLC. The transcriptomic data and clinicopathological data of NSCLC and cancer-adjacent normal tissues were downloaded from the Cancer Genome Atlas (TCGA) database and the immune-related genes were obtained from the IMMPORT database (http://www.immport.org/); then, the differentially expressed immune genes were screened out. Based on these genes, an immune gene prognosis model was constructed. The Cox proportional hazards regression model was used for univariate and multivariate analyses. Further, the correlations among the risk score, clinicopathological characteristics, tumor microenvironment, and the prognosis of NSCLC were analyzed. A total of 193 differentially expressed immune genes related to NSCLC were screened based on the "wilcox.test" in R language, and Cox single factor analysis showed that 19 differentially expressed immune genes were associated with the prognosis of NSCLC (P < 0.05). After including 19 differentially expressed immune genes with P < 0.05 into the Cox multivariate analysis, an immune gene prognosis model of NSCLC was constructed (it included 13 differentially expressed immune genes). Based on the risk score, the samples were divided into the high-risk and low-risk groups. The Kaplan–Meier survival curve results showed that the 5-year overall survival rate in the high-risk group was 32.4%, and the 5-year overall survival rate in the low-risk group was 53.7%. The receiver operating characteristic model curve confirmed that the prediction model had a certain accuracy (AUC = 0.673). After incorporating multiple variables into the Cox regression analysis, the results showed that the immune gene prognostic risk score was an independent predictor of the prognosis of NSCLC patients. There was a certain correlation between the risk score and degree of neutrophil infiltration in the tumor microenvironment. The NSCLC immune gene prognosis assessment model was constructed based on bioinformatics methods, and it can be used to calculate the prognostic risk score of NSCLC patients. Further, this model is expected to provide help for clinical judgment of the prognosis of NSCLC patients.

Identification of SRXN1 and KRT6A as Key Genes in Smoking-Related Non-Small-Cell Lung Cancer Through Bioinformatics and Functional Analyses.

BackgroundLung cancer is the leading cause of cancer-related mortality worldwide. Although cigarette smoking is an established risk factor for lung cancer, few reliable smoking-related biomarkers for non-small-cell lung cancer (NSCLC) are available. An improved understanding of these biomarkers would further the development of new biomarker-targeted therapies and lead to improvements in overall patient survival.MethodsWe performed bioinformatic analysis to screened potential target genes, then quantitative PCR, western, siRNA, CCK-8, flow cytometry, tumorigenicity assays in nude mice were performed to validated the function.ResultsIn this study, we identified 83 smoking-related genes (SRGs) based on an integration analysis of two Gene Expression Omnibus (GEO) datasets, and 27 hub SRGs with potential carcinogenic effects by analyzing a dataset of smokers with NSCLC in The Cancer Genome Atlas (TCGA) database. A survival analysis revealed three genes with potential prognostic value, namely SRXN1, KRT6A and JAKMIP3. A univariate Cox analysis revealed significant associations of elevated SRXN1 and KRT6A expression with prognosis. A receiver operating characteristic (ROC) curve analysis indicated the high diagnostic value of SRXN1 and KRT6A for smoking and cancer. Quantitative PCR and western blotting validated the increased expression of SRXN1 and KRT6A mRNA and protein, respectively, in lung cancer cell lines and NSCLC tissues. In patients with NSCLC, SRXN1 and KRT6A expression was associated with the tumor–node–metastasis (TNM) stage, presence of metastasis, history of smoking and daily smoking consumption. Furthermore, inhibition of SRXN1 or KRT6A suppressed viability and enhanced apoptosis in the A549 human lung carcinoma cell line. Tumorigenicity assays in nude mice confirmed that the siRNA-mediated downregulation of SRXN1 and KRT6A expression inhibited tumor growth in vivo.ConclusionsIn summary, SRXN1 and KRT6A act as oncogenes in NSCLC and might be potential biomarkers of smoking exposure and the early diagnosis and prognosis of NSCLC in smokers, which is vital for lung cancer therapy.

Relevance of multi-disciplinary team approach in diagnosis and management of Stage III NSCLC.

Lung cancer is reported as the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) constitutes 80%-85% of all lung cancers. Diagnosis of NSCLC is a complex multistep process. The prognosis of NSCLC is poor as most of the patients are presented at the metastatic stage. The management of these patients needs the expertise of different specialists. A multidisciplinary team (MDT) comprising specialists from different disciplines has a substantial role in improving outcomes in these patients. This is feasible through extensive discussions, accurate evaluation of patients, reviewing medical records, implementing ideal treatment strategies, and merging local treatments with systemic treatment concepts. Therefore, the MDT approach for stage III NSCLC management can enable early treatment initiation, optimal treatment modalities, and reduce healthcare expenditure. Studies have shown that MDT can provide multimodality care facilitating the diagnosis and treatment of stage III NSCLC, resulting in survival benefit of these patients. Thus, it is imperative to collate scientific evidence to get an insight into the MDT approach in advanced NSCLC treatment. This review aims to summarize the impact of MDT on treatment rates, survival outcome, treatment guideline adherence, and quality of life (QoL) of stage III NSCLC patients.

Novel mutation signatures in the prognosis of EGFR-TKIs targeted therapy for non-small cell lung cancer patients based on the 1000-gene panel sequencing.

The application of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) may be affected by somatic mutations. The purpose of this study was to explore the effect of mutations on the prognosis and tumor markers of NSCLC patients treated with EGFR-TKIs. 21 NSCLC patients treated with EGFR-TKIs were selected, and the targeted sequencing of the tumor tissues or whole blood samples with the 1000-gene panel was conducted to screen mutations. Afterward, functional enrichment analysis was performed based on mutant genes. Subsequently, the correlation between mutations and clinical indicators, prognosis, and tumor markers were analyzed. Finally, the prognosis after taking osimertinib was compared between NSCLC patients with EGFR p.T790M positive and negative mutations, and the EGFR p.T790M concomitant and uncommon mutations were screened. A total of 485 mutations in 251 genes were identified, in which MTOR, AXIN2, AR, EGFR, NOTCH1, and HRAS mutations were significantly correlated with PFS and/or tumor markers. There was no significant difference in PFS, therapeutic effect, and prognosis between EGFR p.T790M positive and negative patients who received osimertinib treatment. Besides, we also found 80 concomitant mutations and 54 uncommon mutations of EGFR p.T790M. AR, HRAS, EGFR, AXIN2, NOTCH1, and MTOR might be key genes to the prognosis of NSCLC treated with EGFR-TKIs. Osimertinib has certain efficacy in EGFR p.T790M negative NSCLC patients.

LINC00628 is differentially expressed between lung adenocarcinoma and squamous cell carcinoma and is associated with the prognosis of NSCLC.

Non-small cell lung cancer (NSCLC) remains the most frequent malignancy worldwide, and lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) represent two major subtypes. LINC00628 has been demonstrated to promote LUAD progression; however, its clinical role in NSCLC remains elusive. The aim of the present study was to analyze the expression of long intergenic non-protein coding RNA 628 (LINC00628) in NSCLC, including in the LUAD and LUSC subtypes. In addition, its roles in NSCLC development and prognosis were also examined. Data from The Cancer Genome Atlas (TCGA) database were first used to assess the expression and prognostic potential in both LUAD and LUSC, then LINC00628 expression in 128 NSCLC tissues was measured using reverse transcription-quantitative PCR. A receiver operating characteristic curve was used to assess the ability of LINC00628 to discriminate between patients with LUAD and LUSC. Kaplan-Meier curves were used to analyze the relationship between LINC00628 expression and the overall survival of patients. Cox regression analysis was used to explore the potential prognostic factors that might be independently associated with NSCLC overall survival. Both in silico and tissue analysis data indicated that the expression of LINC00628 was significantly upregulated in NSCLC tissue compared with matched normal controls (P<0.001). LINC00628 expression levels were also significantly higher in LUAD cases than in patients with LUSC (P<0.001). In addition, LINC00628 could discriminate LUAD from LUSC cases. The expression of LINC00628 was significantly associated with tumor size (P=0.013), histological type (P=0.009), lymph node metastasis (P=0.021) and TNM stage (P=0.008). Survival analysis based on data from both TCGA and patients included in the present study identified an association between LINC00628 and overall survival in LUAD, but this relationship was not observed in LUSC for TCGA data. Cox regression analysis demonstrated that high LINC00628 expression was associated with poor overall survival in patients with LUAD (P=0.001), but not in patients with LUSC (P=0.088). In conclusion, LINC00628 expression was upregulated in NSCLC and associated with patient prognosis. Patients with LUAD had higher LINC00628 expression levels than those with LUSC, and increased LINC00628 served as an independent prognostic factor in LUAD, but not LUSC.

Comprehensive analysis of an immune infiltrate-related competitive endogenous RNA network reveals potential prognostic biomarkers for non-small cell lung cancer.

Globally, non-small cell lung cancer (NSCLC) is the most common malignancy and its prognosis remains poor because of the lack of reliable early diagnostic biomarkers. The competitive endogenous RNA (ceRNA) network plays an important role in the tumorigenesis and prognosis of NSCLC. Tumor immune microenvironment (TIME) is valuable for predicting the response to immunotherapy and determining the prognosis of NSCLC patients. To understand the TIME-related ceRNA network, the RNA profiling datasets from the Genotype-Tissue Expression and The Cancer Genome Atlas databases were analyzed to identify the mRNAs, microRNAs, and lncRNAs associated with the differentially expressed genes. Weighted gene co-expression network analysis revealed that the brown module of mRNAs and the turquoise module of lncRNAs were the most important. Interactions among microRNAs, lncRNAs, and mRNAs were prognosticated using miRcode, miRDB, TargetScan, miRTarBase, and starBase databases. A prognostic model consisting of 13 mRNAs was established using univariate and multivariate Cox regression analyses and validated by the receiver operating characteristic (ROC) curve. The 22 immune infiltrating cell types were analyzed using the CIBERSORT algorithm, and results showed that the high-risk score of this model was related to poor prognosis and an immunosuppressive TIME. A lncRNA–miRNA–mRNA ceRNA network that included 69 differentially expressed lncRNAs (DElncRNAs) was constructed based on the five mRNAs obtained from the prognostic model. ROC survival analysis further showed that the seven DElncRNAs had a substantial prognostic value for the overall survival (OS) in NSCLC patients; the area under the curve was 0.65. In addition, the high-risk group showed drug resistance to several chemotherapeutic and targeted drugs including cisplatin, paclitaxel, docetaxel, gemcitabine, and gefitinib. The differential expression of five mRNAs and seven lncRNAs in the ceRNA network was supported by the results of the HPA database and RT-qPCR analyses. This comprehensive analysis of a ceRNA network identified a set of biomarkers for prognosis and TIME prediction in NSCLC.

Clinical features and prognostic factors of combined small cell lung cancer: development and validation of a nomogram based on the SEER database.

BackgroundCombined small-cell lung cancer (CSCLC) refers to the simultaneous presence of small cell lung cancer (SCLC) and any subtype of the non-small cell lung cancer (NSCLC). This study aimed to explore the prognosis of CSCLC, NSCLC, and pure SCLC patients, and to develop a nomogram to estimate the overall survival (OS) for CSCLC patients.MethodsPatients diagnosed with NSCLC, CSCLC, and pure SCLC between 2004 and 2015 were identified from the Surveillance Epidemiology and End Results (SEER) database. Survival analyses were performed by using the Kaplan Meier curves and Cox proportional hazards regression. All CSCLC patients were randomly split 7:3 into training and validation sets. A nomogram was developed by integrating all independent predictors for OS. The performance of the nomogram was determined by discrimination, calibration ability, clinical usefulness, and risk stratification ability.ResultsA total of 326,695 lung cancer patients, including 871 with CSCLC, 280,391 with NSCLC, and 45,433 with pure SCLC were enrolled. CSCLC was associated with worse survival compared with NSCLC both in the unmatched and matched cohorts. However, compared to pure SCLC, CSCLC was associated with significantly better survival in the unmatched cohorts only, while showed marginally non-significantly better survival after propensity score matching (PSM). For CSCLC, a nomogram was constructed for the 6-month, 1-year, and 3-year OS prediction by combining the independent risk factors, including age, gender, tumor, node, and metastasis stage, surgery, and chemotherapy. The nomogram showed good discrimination and calibration both in the training and validation sets, and better performance than the tumor–node–metastasis staging system. Risk stratification analysis indicated that the nomogram scores efficiently divided CSCLC patients into low-, intermediate-, and high-risk groups (P<0.001).ConclusionsCSCLC patients presented a significantly worse prognosis than patients with NSCLC, but comparable prognosis when compared with pure SCLC patients in the matched cohorts. In addition, we developed and validated a nomogram for predicting the 6-month, 1-year, and 3-year OS in CSCLC patients.

Expression of interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) in non-small cell lung cancer and its relationship with the occurrence and prognosis of cancer pain.

To analyze the expression of interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) in non-small cell lung cancer (NSCLC) and its relationship with the occurrence and prognosis of cancer pain. A total of 113 NSCLC patients (NSCLC group) in People's Hospital of Pengzhou from March 2019 to March 2020 were enrolled, and 109 healthy volunteers (control group) in the same period were selected. The expression levels of IL-1, IL-6, and TNF-α in different populations and in patients with different degrees of cancer pain were compared. Pearson test was used to analyze the correlation between IL-1, IL-6, TNF-α and cancer pain. Multivariate logistic regression was used to analyze the risk factors affecting the poor prognosis of NSCLC patients. Receiver operating characteristic (ROC) curve was drawn to analyze the predictive value of IL-1, IL-6 and TNF-α for poor prognosis of NSCLC. The levels of IL-1, IL-6, and TNF-α in the NSCLC group were significantly higher than those in the control group (P<0.05). According to the Visual Analogue Scale (VAS) scores, 61 cases were divided into the mild group (VAS ≤3 points) and 52 cases were divided into the severe group (VAS >3 points). The levels of IL-1, IL-6, and TNF-α in the severe group were significantly higher than those in the mild group (P<0.05). Multivariate logistic regression analysis showed that clinical stage, lymph node metastasis, differentiation, and IL-1, IL-6, and TNF-α levels were independent risk factors for the poor prognosis of NSCLC patients (P<0.05). Age, sex, and tumor diameter were not prognostic risk factors (P>0.05). The sensitivity and specificity of IL-1 + IL-6 + TNF-α combined for the prediction of poor prognosis of NSCLC were 81.80% and 71.40%, respectively, while the AUC was 0.846 (95% CI: 0.753-0.929), which was significantly higher than that predicted by IL-1, IL-6, and TNF-α alone (P<0.05). The expression levels of IL-1, IL-6, and TNF-α in NSCLC patients were significantly up-regulated, and were closely related to the occurrence and prognosis of cancer pain in patients.