Prognosis Of Non-small Cell Lung Cancer Research Articles

Establishment of Reference Intervals of Cytokeratin 19 Fragment Antigen 21-1 in Korean Adults.

Cytokeratin 19 fragment antigen 21-1 (CYFRA 21-1) is useful for predicting and monitoring non-small cell lung cancer prognosis. We established reference intervals (RIs) of CYFRA 21-1 in Korean adults, including those older than 60 years. Data of 4,098 apparently healthy subjects (age range, 20-87 years) were analyzed after excluding those with a history of malignancy, high tumor marker concentrations (except CYFRA 21-1), and/or abnormal findings on a chest computed tomography scan through medical chart review. After removing two outliers, RIs of CYFRA 21-1 were determined using data of 4,096 subjects based on the non-parametric method (2.5th and 97.5th percentiles) according to CLSI guidelines EP28-A3c. The subjects were divided into two and four groups according to sex and age (20-40, 41-50, 51-60, and >60 years), respectively, and the median CYFRA 21-1 concentration was compared between the groups. The RI of CYFRA 21-1 was 0.66-3.84 ng/mL, applicable to both men and women. Regardless of sex, the CYFRA 21-1 concentration increased with age, suggesting that age-dependent RIs of CYFRA 21-1 should be applied. Rather than using a single RI provided by the manufacturer, the RI of CYFRA 21-1 should be continually verified and established in each clinical laboratory.

EP08.01-093 ICI in Combination With Chemotherapy or Anti-angiogenic Agents as Second-Line Orbeyondtreatment for Advanced Non-small Cell Lung Cancer

Immune checkpoint inhibitors (ICIs), which are currently used in the standard second-line treatment for non-small cell lung cancer (NSCLC), have largely improved the prognosis of advanced NSCLC. However, patients treated with ICI monotherapy have low response rates; hence, there is an urgent need to expand the population responding to immunotherapy treatment. This study aimed to explore the efficacy and safety of the combination of ICI with chemotherapy or anti-angiogenic therapy compared to ICI monotherapy in patients previously treated for advanced NSCLC.

EP03.01-002 Co-occurring Mutations, Smoking Status and Prognosis of Early-stage Resected NSCLCs with EGFR Mutations

Co-occurring pathological mutations in non-small cell lung cancer (NSCLC) may account for clinical heterogeneity not explained by the single driver mutation model. The prognostic significance of various co-mutations and adjuvant treatment modalities has been explored in early-stage NSCLC, but there has not been a focus on the impact of smoking and EGFR co-mutations in early-stage NSCLC. This study aims to characterize the frequency of co-mutations in EGFR-mutated (EGFRm) early-stage resected NSCLC; to describe relationships between smoking history and co-mutation status; and to determine whether prognosis differs by co-mutation status and smoking status among patients with EGFRm NSCLC.

MA04.04 The Ground-Glass Component Status Combined with the Clinical T Descriptor Predicts Prognosis and Genomic Alterations in NSCLC

This single-institution retrospective study investigated whether adding the ground-glass component status from high-resolution computed tomography (HRCT) to the T descriptor of the TNM classification serves as a better predictive factor for prognosis in non-small cell lung cancer (NSCLC). In addition, we asked whether the ground-glass component status is related to genetic markers of the cancer.

Molecular Characteristics and the Effect of KRAS Mutation on the Prognosis of Immunotherapy in Non-Small Cell Lung Cancer in Xinjiang, China.

PurposeNon-small cell lung cancer (NSCLC) is a malignant tumor with high mortality. The Kirsten rat sarcoma vial oncogene (KRAS) gene can affect patient prognosis. In this study, we aim to explore the impact of KRAS mutation status on the clinical prognosis of NSCLC immunotherapy.Patients and MethodsCollected tumor samples from the Affiliated Cancer Hospital of Xinjiang Medical University and 220 patients with stage III–IV NSCLC were included the study. All patients are on first- or second-line therapy and not on targeted therapy. Based on the molecular profiles and clinical features, we analysis of the effect of KRAS mutation on the treatment outcome of NSCLC.ResultsIn this study, the main mutant subtypes of KRAS were G12C, G12D, and G12V. In the KRAS mutation group, the highest mutation frequency other than KRAS was TP53, followed by STK11 and KMT2C. We found that among patients received immunotherapy, KRAS-mutant patients were more sensitive to immunotherapy, with an objective response rate (ORR) of 65% and a disease control rate (DCR) of 80%. Survival analysis found that patients with KRAS mutation had better prognosis with immunotherapy than the non-KRAS mutation patients by comparing the overall survival (OS) (median OS: 18.1 months vs 12.2 months, p=0.0032) and progression-free survival (PFS) (media PFS: 7.9 months vs 3.6 months, p=0.01). We found that the patients with KRAS mutation had better prognosis with immunotherapy than with chemotherapy (median OS: 18.1 months vs 12.3 months, p=0.039, PFS 7.9 months vs 4.1 months, p=0.001). Patients with the KRAS G12C mutation had better results with immunotherapy than chemotherapy, but there was no significant difference in outcome between the two groups (OS: p=0.26 PFS: p=0.055). KRAS and TP53 co-mutation and KRAS and KMT2C co-mutation may improve response to immunotherapy.ConclusionOur results suggested that the gene mutation profile of NSCLC in KRAS mutation group and non-KRAS mutation group were different. The patients with KRAS mutation will have better prognosis with immunotherapy.

Pyroptosis-Related Gene Model Predicts Prognosis and Immune Microenvironment for Non-Small-Cell Lung Cancer.

Non-small-cell lung cancer (NSCLC) has a high incidence and mortality worldwide. Moreover, it needs more accurate means for predicting prognosis and treatments. Pyroptosis is a novel form of cell death about inflammation which was highly related to the occurrence and development of tumors. Despite having some studies about pyroptosis-related genes (PRGs) and cancer, the correlation has not been explored enough between PRGs and immune in NSCLC. In this study, we constructed a PRG model by WGCNA to access the prognosis value PRGs have. The testing cohort (n = 464) with four datasets from the GEO database conducted a survival analysis to confirm the stability of the prognostic model. The risk score and age are examined as independent prognostic factors. Based on the PRGs, we found multiple pathways enriched in immune in NSCLC. Separating samples into three subtypes by consensus cluster analysis, Cluster 3 was identified as immune-inflamed phenotype with an optimistic prognostic outcome. A three-gene PRG signature (BNIP3, CASP9, and CAPN1) was identified, and BNIP3 was identified as the core gene. Knockdown of BNIP3 significantly inhibited the growth of H358 cells and induced pyroptosis. In conclusion, the model construction based on PRGs provides novel insights into the prediction of NSCLC prognosis, and BNIP3 can serve as a diagnostic biomarker for NSCLC.

The Sponge Interaction Between Circular RNA and microRNA Serves as a Fast-Evolving Mechanism That Suppresses Non-small Cell Lung Cancer (NSCLC) in Humans.

Non-small cell lung cancer (NSCLC) is one of the most lethal cancer types in the world. Currently, the molecular mechanisms and pathways underlying NSCLC oncogenesis are poorly understood. Using multiple Omics data, we systematically explored the differentially expressed circular RNAs (circRNAs) in NSCLC. We also investigated potential microRNA sponges (that absorb circRNAs) in NSCLC and downstream target genes with experimental verifications. hsa_circ_0003497 was down-regulated in NSCLC and played an inhibitory role in tumorigenesis. In contrast, miR-197-3p was up-regulated in NSCLC. hsa_circ_0003497 directly interacts with miR-197-3p and releases a target gene of miR-197-3p termed CTNND1 (a known tumor suppressor gene). Evolutionary analysis reveals fast evolution of this hsa_circ_0003497-miR-197-3p-CTNND1-NSCLC axis in mammals. This work clarified the biological functions and molecular mechanisms of how hsa_circ_0003497 suppresses NSCLC through miR-197-3p and CTNND1. We discovered molecular markers for the prognosis of NSCLC and provided potential intervention targets for its treatment.

Transcriptomic and immunologic implications of the epithelial-mesenchymal transition model reveal a novel role of SFTA2 in prognosis of non-small-cell lung carcinoma.

Non-small-cell lung cancer (NSCLC) is the second most common cancer worldwide, and most deaths are associated with epithelial–mesenchymal transition (EMT). Therefore, this study aimed to explore the role of EMT-related transcriptomic profiles in NSCLC and the effect of EMT-based signatures on clinical diagnosis, prognosis, and treatment responses for patients with NSCLC. After integrating the transcriptomics and clinicopathological data, we first constructed EMT clusters (C1 and C2) using machine learning algorithms, found the significant relationship between EMT clusters and survival outcomes, and then explored the impact of EMT clusters on the tumor heterogeneity, drug efficiency, and immune microenvironment of NSCLC. Prominently, differential-enriched tumor-infiltrated lymphocytes were found between EMT clusters, especially the macrophages and monocyte. Next, we identified the most significantly down-regulated gene SFTA2 in the EMT clusters C2 with poor prognosis. Using RT-qPCR and RNA-seq data from the public database, we found prominently elevated SFTA2 expression in NSCLC tissues compared with normal lung tissues, and the tumor suppressor role of SFTA2 in 82 Chinese patients with NSCLC. After Cox regression and survival analysis, we demonstrated that higher SFTA2 expression in tumor samples significantly predicts favorable prognosis of NSCLC based on multiple independent cohorts. In addition, the prognostic value of SFTA2 expression differs for patients with lung adenocarcinoma and squamous cell carcinoma. In conclusion, this study demonstrated that the EMT process is involved in the malignant progression and the constructed EMT clusters exerted significant predictive drug resistance and prognostic value for NSCLC patients. In addition, we first identified the high tumoral expression of SFTA2 correlated with better prognosis and could serve as a predictive biomarker for outcomes and treatment response of NSCLC patients.

Clinical and Biological Significances of a Ferroptosis-Related Gene Signature in Lung Cancer Based on Deep Learning.

Acyl-CoA synthetase long-chain family member 4 (ACSL4) has been linked to the occurrence of tumors and is implicated in the ferroptosis process. Deep learning has been applied to many areas in health care, including imaging diagnosis, digital pathology, classification of cancer, and prediction of metastasis. Nonetheless, neither the level of ACSL4 expression nor its predictive significance in non-small-cell lung cancer (NSCLC) is well understood at this time. Predictions of the ACSL4 mRNA expressions in NSCLC and its link to NSCLC prognosis were made with the aid of the Oncomine and TCGA databases. By performing real-time PCR, we detected the levels of ACSL4 expression that were present in human NSCLC samples. Analyses of the diagnostic, as well as the prognostic significance of ACSL4 in NSCLC, were performed with the use of Kaplan-Meier curves. To assess the influence of ACSL4 on ferroptosis in NSCLC cell lines, an inducer of ferroptosis, namely, erastin, was utilized in this study. In NSCLC tissues, there was a substantial decrease in the level of ACSL4 expression (p < 0.001), and this was in line with the findings of the inquiry into the Oncomine and TCGA databases. After that, the findings of the immunohistochemistry analysis revealed that the ACSL4 staining was weakened in NSCLC samples in contrast with the normal samples. It was shown that the differential expression of ACSL4 was substantially linked to the stages of cancer, smoking behaviors, and the status of nodal metastases (all p < 0.001). According to the findings of the survival analysis, both RFS and OS were favorable among NSCLC patients who had elevated expression of ACSL4. The ferroptosis sensitization in cancer cells may be reestablished with upregulation of ACSL4 through gene transfection. Mechanistically, protein ubiquitination could perform a remarkable function in ACSL4-induced ferroptosis. ACSL4, which has a function in ferroptosis as both a contributor and monitor, was shown to be downregulated in NSCLC. This finding suggests that ACSL4 might function as a helpful diagnostic and prognostic biological marker and might also be considered a novel possible treatment target for NSCLC.

A novel meta-analysis based on data augmentation and elastic data shared lasso regularization for gene expression

BackgroundGene expression analysis can provide useful information for analyzing complex biological mechanisms. However, many reported findings are unrepeatable due to small sample sizes relative to a large number of genes and the low signal-to-noise ratios of most gene expression datasets.ResultsMeta-analysis of multi-data sets is an efficient method for tackling the above problem. To improve the performance of meta-analysis, we propose a novel meta-analysis framework. It consists of two parts: (1) a novel data augmentation strategy. Various cross-platform normalization methods exist, which can preserve original biological information of gene expression datasets from different angles and add different “perturbations” to the dataset. Using such perturbation, we provide a feasible means for gene expression data augmentation; (2) elastic data shared lasso (DSL-{{varvec{L}}}_{mathbf{2}}). The DSL-{mathbf{L}}_{mathbf{2}} method spans the continuum between individual models for each dataset and one model for all datasets. It also overcomes the shortcomings of the data shared lasso method when dealing with highly correlated features. Comprehensive simulation experiment results show that the proposed method has high prediction and gene selection performance. We then apply the proposed method to non-small cell lung cancer (NSCLC) blood gene expression data in order to identify key tumor-related genes. The outcomes of our experiment indicate that the method could be used for identifying a set of robust disease-related gene signatures that may be used for NSCLC early diagnosis or prognosis or even targeting.ConclusionWe propose a novel and effective meta-analysis method for biological research, extrapolating and integrating information from multiple gene expression datasets.

A SERS microfluidic chip based on hpDNA-functioned Au-Ag nanobowl array for efficient simultaneous detection of non-small cell lung cancer-related microRNAs

In this paper, a novel surface-enhanced Raman scattering (SERS) microfluidic chip is proposed for the simultaneous and efficient detection of miR-92a and miR-339-3p, two microRNAs (miRNAs) related to non-small cell lung cancer (NSCLC). The sample solution can flow along the microchannel into the reaction zone during the assay, driven by the capillary force generated by the comb-like structured channel. A one-step paired hybridization reaction with the corresponding hairpin DNA (hpDNA) on the hpDNA-functioned Au-Ag nanobowl (Au-AgNBs) array takes place when the target strand is present in the sample solution, amplifying the SERS signal. The detection limits of miR-92a and miR-339-3p in serum were 44.36 aM and 63.58 aM, respectively, using this method, with a detection and analysis time of only 8 min. The microfluidic chip showed good specificity, reproducibility, and stability. Finally, the method was used to detect miR-92a and miR-339-3p in the serum of NSCLC clinical samples, and the results were consistent with the quantitative real-time polymerase chain reaction (qRT-PCR). In conclusion, this new SERS microfluidic chip is a very promising tool for detecting miRNA expression levels, which can help in the early diagnosis and prognosis of NSCLC.

Tumor-infiltrating neutrophils and peripheral neutrophil-to-lymphocyte ratio conversely predicted the prognosis of patients with non-small cell lung cancer

Increasing evidence indicates that neutrophil-associated prognostic markers, such as, tumor-associated neutrophils (TANs), neutrophil-to-T cell ratio (NTR) and neutrophil-to-lymphocyte ratio (NLR), are strongly correlated with the survival of patients with non-small cell lung cancer (NSCLC). However, either the association or the difference in their predictive efficacies remains unknown. To this aim, we investigated the influence of intratumoural TANs and peripheral NLR on the clinical outcome of NSCLC patients using tumor tissues, peripheral blood indexes, and clinicopathological data of 133 patients diagnosed with NSCLC. Additionally, Kendall correlation analysis was performed to identify the association between TANs and NLR. Our results revealed that intratumoural TANs were effective prognostic factors for favorable overall survival (OS), but were not associated with disease-free survival (DFS) in the subgroup analysis of 84 postoperative patients and progression-free survival (PFS) in 49 non-resectable NSCLC patients. Elevated NTR also indicated favorable prognosis, with high intratumoural NTR being correlated with prolonged OS and high stromal NTR being correlated with prolonged DFS. In contrast, peripheral NLR predicted dismal OS and DFS of patients receiving curative surgery. Furthermore, neither intratumoural nor stromal TANs were found to be associated with NLR, indicating that they were independent inflammatory indexes in predicting the prognosis of NSCLC. In conclusion, we discovered that TANs and NLR independently and oppositely predicted the clinical outcome of NSCLC patients, providing new sights on the role of neutrophil in tumor biology and survival prediction.

Novel GIRlncRNA Signature for Predicting the Clinical Outcome and Therapeutic Response in NSCLC.

Background: Non–small cell lung cancer (NSCLC) is highly malignant with driver somatic mutations and genomic instability. Long non-coding RNAs (lncRNAs) play a vital role in regulating these two aspects. However, the identification of somatic mutation-derived, genomic instability-related lncRNAs (GIRlncRNAs) and their clinical significance in NSCLC remains largely unexplored. Methods: Clinical information, gene mutation, and lncRNA expression data were extracted from TCGA database. GIRlncRNAs were screened by a mutator hypothesis-derived computational frame. Co-expression, GO, and KEGG enrichment analyses were performed to investigate the biological functions. Cox and LASSO regression analyses were performed to create a prognostic risk model based on the GIRlncRNA signature (GIRlncSig). The prediction efficiency of the model was evaluated by using correlation analyses with mutation, driver gene, immune microenvironment contexture, and therapeutic response. The prognostic performance of the model was evaluated by external datasets. A nomogram was established and validated in the testing set and TCGA dataset. Results: A total of 1446 GIRlncRNAs were selected from the screen, and the established GIRlncSig was used to classify patients into high- and low-risk groups. Enrichment analyses showed that GIRlncRNAs were mainly associated with nucleic acid metabolism and DNA damage repair pathways. Cox analyses further identified 19 GIRlncRNAs to construct a GIRlncSig-based risk score model. According to Cox regression and stratification analyses, 14 risk lncRNAs (AC023824.3, AC013287.1, AP000829.1, LINC01611, AC097451.1, AC025419.1, AC079949.2, LINC01600, AC004862.1, AC021594.1, MYRF-AS1, LINC02434, LINC02412, and LINC00337) and five protective lncRNAs (LINC01067, AC012645.1, AL512604.3, AC008278.2, and AC089998.1) were considered powerful predictors. Analyses of the model showed that these GIRlncRNAs were correlated with somatic mutation pattern, immune microenvironment infiltration, immunotherapeutic response, drug sensitivity, and survival of NSCLC patients. The GIRlncSig risk score model demonstrated good predictive performance (AUCs of ROC for 10-year survival was 0.69) and prognostic value in different NSCLC datasets. The nomogram comprising GIRlncSig and tumor stage exhibited improved robustness and feasibility for predicting NSCLC prognosis. Conclusion: The newly identified GIRlncRNAs are powerful biomarkers for clinical outcome and prognosis of NSCLC. Our study highlights that the GIRlncSig-based score model may be a useful tool for risk stratification and management of NSCLC patients, which deserves further evaluation in future prospective studies.

Effect of PFKFB4 on the Prognosis and Immune Regulation of NSCLC and Its Mechanism.

BackgroundNSCLC (non-small cell lung cancer) has become the malignancy with the highest incidence and mortality rate worldwide. Fructose-6-phosphate 2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is a key regulator of glycolysis with both kinase and phosphatase activities. The Warburg effect, or increased glycolysis in tumors, provides the metabolic basis for cancer cell proliferation and metastasis, and the Warburg pathway enzyme PFKFB4 is a newly identified important kinase. This study aimed to elucidate the poor prognostic relevance of PFKFB4 in non-small cell lung cancer tissues and its relationship with immune cell infiltration, immune cell biomarkers, and immune checkpoints.MethodsIn this study, immunohistochemical methods were used to assess PFKFB4 expression levels in 140 surgical specimens from patients with histologically confirmed non-small cell lung cancer and to investigate the relationship between PFKFB4 expression levels and the patients’ clinicopathological characteristics. The impact of PFKFB4 expression on prognosis was evaluated using Kaplan–Meier survival analysis and Cox regression analysis.ResultsWhen compared to normal paracrine tissues, PFKFB4 expression was enhanced in lung cancer tissues, and Kaplan–Meier survival analysis revealed that patients with high PFKFB4 expression had a worse prognosis. In NSCLC, PFKFB4 was found to be associated with immune cell infiltration and immunological checkpoints.ConclusionPFKFB4 expression may be upregulated as a sign of poor prognosis in NSCLC, and PFKFB4 may be implicated not only in the genesis and progression of NSCLC but also in its immunological control.

Long-term clinical outcomes and prognostic factors of upfront surgery as a first-line therapy in biopsy-proven clinical N2 non-small cell lung cancer.

BackgroundMultimodality therapy offers the best opportunity to improve pathological N2 non-small cell lung cancer (NSCLC) prognosis. This paper aimed to evaluate the long-term clinical outcomes and the prognostic factors of upfront surgery as first-line therapy in biopsy-proven clinical N2.MethodsRetrospective review of biopsy-proven cN2 NSCLC patients operated between 2007 and 2017. Upfront surgery was considered if the primary tumour was deemed completely resectable, with mediastinal nodal involvement confined to a single station and no preoperative evidence of extranodal tumour invasion.ResultsTwo hundred eighty-five patients who underwent radical resections were included. One hundred fifty-nine patients (55.8%) received induction chemotherapy. At follow-up completion, 127 (44.6%) patients had died. For the induction chemotherapy group, the median overall survival (OS) was 49 months [95% confidence interval (CI): 38–70 months], and the 5-year OS was 44.4%. The median and 5-year OS for the up front surgery group was 66 months (95% CI: 40–119 months) and 66.3%, respectively. There were no statistically significant differences between treatment approaches (p = 0.48). One hundred thirty-four patients (47.0%) developed recurrence. The recurrence-free survival (RFS) at 5 years was 17% (95% CI: 11–25%) for induction chemotherapy and 22% (95% CI: 9–32%) for upfront surgery; there were no statistically significant differences between groups (p = 0.93). No significant differences were observed based on the clinical N status (OS, p = 0.36; RFS, p = 0.65).ConclusionsUpfront surgery as first-line therapy for biopsy-proven cN2 NSCLC showed favourable clinical outcomes, similar to those obtained after induction chemotherapy followed by surgery. Therefore, it should be considered one of the multimodality treatment options in resectable N2 NSCLC.

The Prognostic Value of Periostin Expression in Non-Small Cell Lung Cancer: A Meta-Analysis.

BackgroundNon-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related death in the world and its poor prognosis is a major concern. Periostin was found to be associated with the prognosis of NSCLC. However, the research results were inconsistent. This meta-analysis evaluated the correlation between periostin expression and the prognosis of NSCLC.Material/MethodsA meta-analysis was performed on data acquired from PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang Database from inception to 18 June 2022. Published and unpublished studies investigating the correlation between periostin expression and the prognosis of NSCLC were included in this meta-analysis. Eligible studies reported at least 1 of the following clinical outcome measures: overall survival, progression-free survival, cancer-specific survival, relapse-free survival, disease-free survival, or other clinical parameters of prognosis. Pooled hazard ratios (HR) with 95% confidence interval (CI) were calculated using the random-effects model. Sensitivity and subgroup analyses and assessment of publication bias were also conducted.ResultsThis meta-analysis enrolled 2504 NSCLC cases from 12 eligible studies. The hazard ratio for the overall survival was 1.761 (95% CI: 1.022–3.033, P=0.041). Heterogeneity was significant among the studies, but publication bias was lacking. Subgroup analyses were performed based on different issues, such as districts, antibodies and methods for periostin detection.ConclusionsOverexpression of periostin is a negative prognostic factor and is associated with worse overall survival (OS) in NSCLC patients. Periostin may serve as a prognostic biomarker for NSCLC patients.

Validation and analysis of expression, prognosis and immune infiltration of WNT gene family in non-small cell lung cancer.

Early diagnosis and prognosis prediction of non-small cell lung cancer (NSCLC) have been challenging. Signaling cascades involving the Wingless-type (WNT) gene family play important biological roles and show prognostic value in various cancers, including NSCLC. On this basis, this study aimed to investigate the significance of WNTs in the prognosis and tumor immunity in NSCLC by comprehensive analysis. Expression and methylation levels of WNTs were obtained from the ONCOMINE, TIMER, and UALCAN. The dataset obtained from The Cancer Genome Atlas (TCGA) was utilized for prognostic analysis. cBioPortal was used to perform genetic alterations and correlation analysis of WNTs. R software was employed for functional enrichment and pathway analysis, partial statistics, and graph drawing. TRRUST was used to find key transcription factors. GEPIA was utilized for the analysis of expression, pathological staging, etc. Correlative analysis of immune infiltrates from TIMER. TISIDB was used for further immune infiltration validation analysis. Compared with that of normal tissues, WNT2/2B/3A/4/7A/9A/9B/11 expressions decreased, while WNT3/5B/6/7B/8B/10A/10B/16 expressions increased in lung adenocarcinoma (LUAD); WNT2/3A/7A/11 expressions were lessened, while WNT2B/3/5A/5B/6/7B/10A/10B/16 expressions were enhanced in squamous cell lung cancer (LUSC). Survival analysis revealed that highly expressed WNT2B and lowly expressed WNT7A predicted better prognostic outcomes in LUAD and LUSC. In the study of immune infiltration levels, WNT2, WNT9B, and WNT10A were positively correlated with six immune cells in LUAD; WNT1, WNT2, and WNT9B were positively correlated with six immune cells in LUSC, while WNT7B was negatively correlated. Our study indicated that WNT2B and WNT7A might have prognostic value in LUAD, and both of them might be important prognostic factors in LUSC and correlated to immune cell infiltration in LUAD and LUSC to a certain extent. Considering the prognostic value of WNT2B and WNT7A in NSCLC, we validated their mRNA and protein expression levels in NSCLC by performing qRT-PCR, western blot, and immunohistochemical staining on NSCLC pathological tissues and cell lines. This study may provide some direction for the subsequent exploration of the prognostic value of the WNTs and their role as biomarkers in NSCLC.

Systematic analysis of expression profiles of HMGB family members for prognostic application in non-small cell lung cancer.

Background: Lung cancer is a significant challenge to human health. Members of the high mobility group (HMG) superfamily (HMGB proteins) are implicated in a wide variety of physiological and pathophysiological processes, but the expression and prognostic value of HMGB family members in non-small cell lung cancer (NSCLC) have not been elucidated. Methods: In this study, ONCOMINE, UALCAN, GEPIA, Kaplan–Meier Plotter, starBase, OncomiR databases, and GeneMANIA were utilized to evaluate the prognostic significance of HMGB family members in NSCLC. Results: HMGB2/3 expression levels were higher in NSCLC patients. HMGB1 expression was higher in lung squamous cell carcinoma (LUSC) and was lower in lung adenocarcinoma (LUAD) tissue than in normal lung tissue. HMGB2 expression was related to cancer stage. Increased HMGB1 mRNA expression levels were associated with improved lung cancer prognosis, including overall survival (OS), first-progression survival (FP), and post-progression survival (PPS). There was no significant association between HMGB2 levels and prognostic indicators. HMGB3 expression was associated with poorer OS. GeneMANIA and GO/KEGG pathway analysis showed that HMGB family members mainly associated with chromosome condensation, regulation of chromatin organization, and nucleosome binding in NSCLC. HMGBs expression were closely correlated with infiltrating levels of specific types of immune cells in NSCLC, especially Th2 cells, Th17 cells, and mast cells. hsa-miR-25-3p, hsa-miR-374a-3p, and hsa-miR-93-5p were significantly positively correlated with HMGB1, HMGB2, and HMGB3, respectively. However, hsa-miR-30a-5p was predicted to significantly negatively regulate HMGB3 expression. Conclusion: Our study revealed that HMGB1 is positively related to the improved prognosis in NSCLC, and demonstrate that HMGB3 might be a risk factor for poorer survival of NSCLC patients.

MiR-495–3p regulates sphingolipid metabolic reprogramming to induce Sphk1/ceramide mediated mitophagy and apoptosis in NSCLC

Sphingolipid metabolism is the forefront area of cancer research, but the underlying mechanisms are not fully explored yet. Sphingolipid metabolites [ceramide, sphingosine-1-phosphate (S1P)] are critical players in cell growth and apoptosis. Sphk1 is a key enzyme, catalyzing the phosphorylation of sphingosine to S1P, favoring cell proliferation and survival. Contrarily, ceramide induces cell cycle arrest and apoptosis. Sphk1 also exerts regulatory roles in numerous cellular processes, wherein microRNAs (miRNAs) play a momentous role. However, miR-mediated regulation of Sphk1 in Non-small cell lung cancer (NSCLC), continues to be elusive. miR-495 is highly downregulated and worsens NSCLC prognosis. The present study demonstrates Sphk1 upregulation and poor prognosis in NSCLC. However, miR-495–3p directly targets Sphk1, and possesses tumor-suppressive roles by decreasing cell proliferation, wound healing, colony formation, LDH-A activity, and inducing G0/G1 phase cell cycle arrest upon restoration. Besides, we also found ceramide accretion upon Sphk1 inhibition, leading to mitochondrial dysregulation. We found a cogent upregulation of Drp-1, PARK2 and LC3β, along with degradation of PINK1 and Mfn2, demonstrating an imbalance in mitochondrial fission/fusion and induction of mitophagy, even during PINK1 deficiency. Later, we found a reduction in mitochondrial energy homeostasis, mitochondrial membrane potential, increased ROS generation and ultimately initiation of apoptosis, upon miR-495–3p overexpression. Overall, we showed that miR-495–3p reprograms sphingolipid rheostat towards ceramide by targeting Sphk1 and induces lethal mitophagy to suppress NSCLC tumorigenesis. The study identified a miR-mediated mechanism of sphingolipid reprogramming that could be beneficial in designing novel therapeutic strategies for NSCLC.

Prognostic predictors of non-small cell lung cancer treated with curative resection: the role of preoperative CT texture features, clinical features, and laboratory parameters

To explore the value of preoperative contrast-enhanced computed tomography (CT) tumour texture characteristics, and clinical and laboratory parameters on the prognosis of curative resection for non-small-cell lung cancer (NSCLC). This retrospective study included 64 patients (34 men and 30 women) with NSCLC who underwent curative resection and were then followed up for 5 years or until death. Preoperative contrast-enhanced CT images, clinical features, and laboratory parameters were collected for these patients. CT texture features of the primary tumour before surgery were extracted from the contrast-enhanced CT images using ImageJ software. Based on the cut-off values determined by X-tile software, the preoperative CT texture features, clinical features, and laboratory parameters were divided into two groups. Kaplan-Meier survival curves and log-rank tests were used to compare the 5-year overall survival (OS) of patients. Multivariate Cox regression analysis was used to determine the independent factors influencing the prognosis. The mean survival was 51.5 months. Tumour volume, entropy, platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), and albumin-to-globulin ratio (AGR) were shown to be significantly associated with 5-year OS (p<0.05). Multivariate Cox regression analysis revealed that entropy was the independent factor of prognosis (hazard ratio 4.375, 95% confidence interval [CI]: 1.646-11.620, p=0.003). Entropy is an important and potentially non-invasive imaging biomarker for predicting the prognosis of NSCLC undergoing curative resection.