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Apoptosis has long been recognized as a significant mechanism for inhibiting tumor formation, and a plethora of stimuli can induce apoptosis during the progression and treatment of tumors. Moreover, tumor-derived apoptotic extracellular vesicles (apoEVs) are inevitably phagocytosed by live tumor cells, promoting tumor heterogeneity. Understanding the mechanism by which apoEVs regulate tumor cells is imperative for enhancing our knowledge of tumor metastasis and recurrence. Herein, we conducted a series of in vivo and in vitro experiments, and we report that tumor-derived apoEVs promoted lung adenocarcinoma (LUAD) metastasis, self-renewal and chemoresistance. Mechanistically, we demonstrated that apoEVs facilitated tumor metastasis and stemness by initiating the epithelial-mesenchymal transition program and upregulating the transcription of the stem cell factor SOX2. In addition, we found that ALDH1A1, which was transported by apoEVs, activated the NF-κB signaling pathway by increasing aldehyde dehydrogenase enzyme activity in recipient tumor cells. Furthermore, targeting apoEVs-ALDH1A1 significantly abrogated these effects. Collectively, our findings elucidate a novel mechanism of apoEV-dependent intercellular communication between apoptotic tumor cells and live tumor cells that promotes the formation of cancer stem cell-like populations, and these findings reveal that apoEVs-ALDH1A1 may be a potential therapeutic target and biomarker for LUAD metastasis and recurrence.

Abstract Lymph node (LN) metastasis is one of the predominant metastatic routes of non-small cell lung cancer (NSCLC) and is considered as a leading cause for the unsatisfactory prognosis of patients. Although lymphangiogenesis is well-recognized as a crucial process in mediating LN metastasis, the regulatory mechanism involving lymphangiogenesis and LN metastasis in NSCLC remains unclear. In this study, we employed high-throughput sequencing to identify a novel circular RNA (circRNA), circTLCD4-RWDD3, which was significantly upregulated in extracellular vesicles (EVs) from LN metastatic NSCLC and was positively associated with deteriorated OS and DFS of patients with NSCLC from multicenter clinical cohort. Downregulating the expression of EV-packaged circTLCD4-RWDD3 inhibited lymphangiogenesis and LN metastasis of NSCLC both in vitro and in vivo. Mechanically, circTLCD4-RWDD3 physically interacted with hnRNPA2B1 and mediated the SUMO2 modification at K108 residue of hnRNPA2B1 by upregulating UBC9. Subsequently, circTLCD4-RWDD3-induced SUMOylated hnRNPA2B1 was recognized by the SUMO interaction motif (SIM) of ALIX and activated ALIX to recruit ESCRT-III, thereby facilitating the sorting of circTLCD4-RWDD3 into NSCLC cell-derived EVs. Moreover, EV-packaged circTLCD4-RWDD3 was internalized by lymphatic endothelial cells to activate the transcription of PROX1, resulting in the lymphangiogenesis and LN metastasis of NSCLC. Importantly, blocking EV-mediated transmission of circTLCD4-RWDD3 via mutating SIM in ALIX or K108 residue of hnRNPA2B1 inhibited the lymphangiogenesis and LN metastasis of NSCLC in vivo. Our findings reveal a precise mechanism underlying SUMOylated hnRNPA2B1-induced EV packaging of circTLCD4-RWDD3 in facilitating LN metastasis of NSCLC, suggesting that EV-packaged circTLCD4-RWDD3 could be a potential therapeutic target against LN metastatic NSCLC.

Abstract Background Serine protease inhibitors clade B serpins (SERPINBs) are the largest subclass of protease inhibitors, once thought of as a tumor suppressor gene family. However, some SERPINBs exhibit functions unrelated to the inhibition of catalytic activity. Methods The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Gene Set Cancer Analysis (GSCA), and cBioPortal databases were utilized to investigate SERPINBs expression, prognostic correlation, and genomic variation in 33 cancer types. We also conducted a comprehensive transcriptome analysis in multiple lung adenocarcinoma (LUAD) cohorts to reveal the molecular mechanism of SERPINB5 in LUAD. Then, qPCR and immunohistochemistry were used to verify the expression and prognostic value of SERPINB5 in LUAD patients. Furthermore, knockdown and overexpression of SERPINB5 in LUAD cell lines were performed to evaluate cell proliferation, migration, invasion, and epithelial‐mesenchymal transition (EMT). Results The expression of SERPINB5 was upregulated and demethylated in LUAD, and its abnormally high expression was significantly correlated with poor overall survival (OS). In addition, the expression of SERPINB5 was analyzed to determine its prognostic value in LUAD and confirmed that SERPINB5 was an independent predictor of LUAD in TCGA and GEO cohorts and qPCR validation with 106 clinical samples. At last, A knockdown of SERPINB5 in LUAD cells reduced proliferation, migration, and EMT. Proliferation, migration, and invasion are promoted by the overexpression of SERPINB5. Conclusion Therefore, SERPINB5 has shown potential as a prognostic biomarker for LUAD, and it may become a potential therapeutic target for lung adenocarcinoma.

BackgroundPrevious studies had demonstrated that marital status was an independent prognostic factor in multiple cancers. However, the impact of marital status on non-small cell lung cancer (NSCLC) patients was still highly controversial.MethodAll NSCLC patients diagnosed between 2010–2016 were selected from the Surveillance, Epidemiology and End Results (SEER) database. To control the confounding effect of related clinicopathological characteristics, propensity score matching (PSM) was conducted between married and unmarried groups. In addition, independent prognostic clinicopathological factors were evaluated via Cox proportional hazard regression. Moreover, nomograms were established based on the clinicopathological characteristics, and the predictive accuracy was assessed by calibration curves. Furthermore, decision curve analysis (DCA) was used to determine the clinical benefits.ResultsIn total, 58,424 NSCLC patients were enrolled according to the selection criteria. After PSM, 20,148 patients were selected into each group for further analysis. The married group consistently demonstrated significantly better OS and CSS compared to unmarried group [OS median survival (95% CI): 25 (24–26) vs. 22 (21–23) months, p

BackgroundLung cancer is one of the cancers with the highest morbidity and mortality. During the last decade, the trends of clinical characteristics, surgical treatments and survival of lung cancer patients in China have remained unclear.MethodsAll lung cancer patients operated on from 2011 to 2020 were identified in a prospectively maintained database of Sun Yat-sen University Cancer Center.ResultsA total of 7,800 lung cancer patients were included in this study. Within the past 10 years, the average age at diagnosis of the patients remained stable, the proportion of asymptomatic, female and nonsmoking patients increased, and the average tumor size decreased from 3.766 to 2.300 cm. In addition, the proportion of early stage and adenocarcinoma increased, while that of squamous cell carcinoma decreased. Among the patients, the proportion of patients having video-assisted thoracic surgery increased. More than 80% of the patients underwent lobectomy and systematic nodal dissection over the 10 years. Additionally, both the average postoperative length of stay and 1-, 3-, and 6-month postoperative mortality decreased. Moreover, the 1-, 3-, and 5-year overall survival (OS) rates of all the operable patients increased from 89.8, 73.9, and 63.8% to 99.6, 90.7, and 80.8%, respectively. The 5-year OS rates of the patients with stage I, II, and III lung cancer were 87.6, 79.9, and 59.9%, respectively, which were higher than those in other published data.ConclusionThere were significant changes in the clinicopathological characteristics, surgical treatments and survival outcomes of the patients with operable lung cancer from 2011 to 2020.

Background Oesophageal squamous cell carcinoma (ESCC) is a malignant tumour of the digestive system that is associated with high morbidity and mortality rates worldwide. With the increased use of immunotherapy in cancer treatment, there is an urgent need to elucidate the immune-related mechanisms in ESCC and other digestive system carcinomas. Methods In our study, single-sample gene set enrichment analysis (ssGSEA) was first performed to analyse the expression profile downloaded from the NCBI Gene Expression Omnibus (GEO) database. Then, via a series of bioinformatic analyses, including the Mann-Whitney test, weighted gene co-expression network analysis (WGCNA), functional enrichment analysis and differentially expressed genes (DEGs) analysis, we identified target immunocytes and related genes. Finally, we validated the results with the TIMER database. Results Our analyses showed that the numbers of infiltrating macrophages were obviously higher in advanced stages in ESCC compared with other types of immunocytes. MEOX2 was identified as a biomarker correlated with macrophage infiltration in ESCC and other types of digestive system carcinomas. And MEOX2 expression was strongly associated with the mRNA expression of colony-stimulating factor 1 (CSF-1) and CSF-1 receptor (CSF-1R) in these kinds of carcinomas. Conclusion We speculated that MEOX2 could facilitate macrophage infiltration via CSF-1/CSF-1R signalling in ESCC and other kinds of digestive system carcinomas, and MEOX2 might serve as a novel target in prospective tumour immunotherapies.

Background: The tumor microenvironment (TME) is involved in the development and progression of lung carcinomas. A deeper understanding of TME landscape would offer insight into prognostic biomarkers and potential therapeutic targets investigation. To this end, we aimed to identify the TME components of lung cancer and develop a prognostic signature to predict overall survival (OS).Methods: Expression data was retrieved from The Cancer Genome Atlas (TCGA) database and differentially expressed TME-related genes were calculated between tumor and normal tissues. Then nonnegative matrix factorization (NMF) clustering was used to identify two distinct subtypes.Results: Our analysis yielded a gene panel consisting of seven TME-related genes as candidate signature set. With this panel, our model showed that the high-risk group experienced a shorter survival time. This model was further validated by an independent cohort with data from Gene Expression Omnibus (GEO) database (GSE50081 and GSE13213). Additionally, we integrated the clinical factors and risk score to construct a nomogram for predicting prognosis. Our data suggested less immune cells infiltration but more fibroblasts were found in tumor tissues derived from patients at high-risk and those patients exhibited a worse immunotherapy response.Conclusion: The signature set proposed in this work could be an effective model for estimating OS in lung cancer patients. Hopefully analysis of the TME could have the potential to provide novel diagnostic, prognostic and therapeutic opportunities.

Introduction: the investigation on the interactions between ferroptosis and lncRNAs for lung squamous cell carcinoma (LUSC) has been scare, and its impact on tumor immune microenvironment remained unknown. We aim to not only identify a ferroptosis-related lncRNAs signature for LUSC prognosis, but also evaluate its correlation to tumor immune evasion.Methods: RNA sequencing data and survival information were obtained from The Cancer Genome Atlas database. A ferroptosis-related lncRNAs signature (FerRLSig) was developed and validated by univariate Cox regression, Least Absolute Shrinkage and Selection Operator regression and multivariate Cox regression. The tumor immune microenvironment and immune evasion were subsequently evaluated based on the FerRLSig stratification.Results: the FerRLSig consisted of 10 ferroptosis-related lncRNAs and significantly associated with overall survival with satisfactory area under curve (HR = 2.240, 95% CI: 1.845–2.720, p < 0.001, 5-years AUC: 0.756). Based on the FerRLSig stratification, the high-risk group demonstrated not only significantly higher immune infiltration, but also more profound T cell dysfunction and immune evasion, which might ultimately lead to the resistance to current immune checkpoint inhibitors.Conclusion: a robust prognostic FerRLSig for LUSC has been developed and validated, demonstrating a close association not only with tumor immune cell infiltration, but also with T cell dysfunction and immune evasion. Further investigation is warranted to better improve the survival of LUSC patients based on the FerRLSig stratification.

Recent studies have highlighted the combination of activation of host immunogenic cell death (ICD) and tumor-directed cytotoxic strategies. However, overall multiomic analysis of the intrinsic ICD property in lung adenocarcinoma (LUAD) has not been performed. Therefore, the aim of this study was to develop an ICD-based risk scoring system to predict overall survival (OS) and immunotherapeutic efficacy in patients. In our study, both weighted gene co-expression network analysis (WGCNA) and LASSO-Cox analysis were utilized to identify ICDrisk subtypes (ICDrisk). Moreover, we identify genomic alterations and differences in biological processes, analyze the immune microenvironment, and predict the response to immunotherapy in patients with pan-cancer. Importantly, immunogenicity subgroup typing was performed based on the immune score (IS) and microenvironmental tumor neoantigens (meTNAs). Our results demonstrate that ICDrisk subtypes were identified based on 16 genes. Furthermore, high ICDrisk was proved to be a poor prognostic factor in LUAD patients and indicated poor efficacy of immune checkpoint inhibitor (ICI) treatment in patients with pan-cancer. The two ICDrisk subtypes displayed distinct clinicopathologic features, tumor-infiltrating immune cell patterns, and biological processes. The ISlowmeTNAhigh subtype showed low intratumoral heterogeneity (ITH) and immune-activated phenotypes and correlated with better survival than the other subtypes within the high ICDrisk group. This study suggests effective biomarkers for the prediction of OS in LUAD patients and immunotherapeutic response across Pan-cancer and contributes to enhancing our understanding of intrinsic immunogenic tumor cell death.

BackgroundGenomic instability is one of the representative features of cancer evolution. Recent research has revealed that long noncoding RNAs (lncRNAs) play a critical role in maintaining genomic instability. Our work proposed a gene signature (GILncSig) based on genomic instability-derived lncRNAs to probe the possibility of lncRNA signatures as an index of genomic instability, providing a potential new approach to identify genomic instability-related cancer biomarkers.MethodsLung adenocarcinoma (LUAD) gene expression data from an RNA-seq FPKM dataset, somatic mutation information and relevant clinical materials were downloaded from The Cancer Genome Atlas (TCGA). A prognostic model consisting of genomic instability-related lncRNAs was constructed, termed GILncSig, to calculate the risk score. We validated GILncSig using data from the Gene Expression Omnibus (GEO) database. In this study, we used R software for data analysis.ResultsThrough univariate and multivariate Cox regression analyses, five genomic instability-associated lncRNAs (LINC01671, LINC01116, LINC01214, lncRNA PTCSC3, and LINC02555) were identified. We constructed a lncRNA signature (GILncSig) related to genomic instability. LUAD patients were classified into two risk groups by GILncSig. The results showed that the survival rate of LUAD patients in the low-risk group was higher than that of those in the high-risk group. Then, we verified GILncSig in the GEO database. GILncSig was associated with the genomic mutation rate of LUAD. We also used GILncSig to divide TP53 mutant-type patients and TP53 wild-type patients into two groups and performed prognostic analysis. The results suggested that compared with TP53 mutation status, GILncSig may have better prognostic significance.ConclusionsBy combining the lncRNA expression profiles associated with somatic mutations and the corresponding clinical characteristics of LUAD, a lncRNA signature (GILncSig) related to genomic instability was established.

Background: Currently, the extent of lymph node evaluation necessary for patients with early-stage non-small-cell lung cancer (NSCLC) remains controversial according to the latest ESMO and NCCN guidelines. In this study, we aimed to evaluate the survival effect of different numbers of lymph nodes examined (LNE) and regions of lymph nodes removed (LNR) in patients with stage IA NSCLC.Method: All patients with stage IA NSCLC undergoing lobectomy or bilobectomy were selected from the surveillance, epidemiology, and end results (SEER) database. The number of LNE and LNR were stratified into 4 groups (0, 1–2, 3–8, and ≥9 lymph nodes) and 3 groups (0, 1–3, and ≥4 regions) respectively. Additionally, the survival curves of overall survival (OS) and cancer-specific survival (CSS) were plotted and compared with the Kaplan-Meier method and log-rank test. Independent prognostic clinicopathological factors were evaluated via Cox proportional hazard regression and subgroup analysis.Results: Totally, 12,490 patients with stage IA NSCLC were enrolled in our study. Patients with ≥9 LNE and ≥4 LNR in both the T1b and T1c stages consistently demonstrated the significantly best OS and CSS outcomes. In the multivariate analysis, patients with ≥9 LNE consistently had a significantly better CSS [hazards ration (HR) (95% CI):0.539 (0.438–0.663)], and those with ≥4 LNR consistently had a significantly better OS [HR (95% CI):0.678 (0.476–0.966)]. Furthermore, ≥9 LNE and ≥4 LNR were associated with better survival in most subgroups.Conclusion: This study demonstrated that ≥9 LNE and ≥4 LNR are highly recommended for stage IA2 and stage IA3 patients but optional for stage IA1 patients.

Background: We previously identified a 12-microRNA (miRNA) panel (miRNA-17, miRNA-146a, miRNA-200b, miRNA-182, miRNA-155, miRNA-221, miRNA-205, miRNA-126, miRNA-7, miRNA-21, miRNA-145, and miRNA-210) that aided in the early diagnosis of non-small cell lung cancer (NSCLC). We validated the diagnostic value of this miRNA panel and compared it with that of traditional tumor markers and radiological diagnosis. We constructed a nomogram based on the miRNA panel's results to predict the risk of NSCLC.Methods: Eighty-two participants with pulmonary nodules on a CT scan and who underwent a pathological examination and surgical treatment were enrolled in our study. Patients were randomly divided into a training group or a validation group. The miRNA concentrations were quantified by RT-PCR and log-transformed for analysis. The cutoff value was determined in the training group and then applied in the validation group. A comparison between the miRNAs and traditional tumor markers [CEA, NSE, and cytokeratin 19 fragment 21-1 (Cyfra21-1)] and radiological diagnosis was performed. A nomogram based on the miRNA panel's results to predict the risk of NSCLC was constructed.Results: The expression level of these 12 miRNAs was significantly higher in NSCLC patients than in benign patients. In the validation group, the specificity and positive predictive value were 96.4 and 95.8%, respectively, which were significantly higher than those using traditional tumor markers or radiological diagnosis. The sensitivity was 42.6%, which was also higher than that using tumor markers. Moreover, the sensitivity increased to 63.6% when the nodule diameters were larger than 2 cm. The miRNAs and seven clinical factors were integrated into the nomogram, and the calibration curves showed optimal agreement between the predicted and actual probabilities.Conclusions: Our miRNA panel has clinical value for the early detection of NSCLC. A nomogram was constructed and internally validated, and the results indicate that it can assist clinicians in making treatment recommendations in the clinic.

Introduction: A certain number of small cell lung cancer (SCLC) patients become long-term survivors after treatment, and they are at high risk to develop a second primary malignancy, including non-small cell lung cancer. However, the optimal management of early-stage second primary non-small cell lung cancer (SPLC) after SCLC remains unknown. This study aims to evaluate the survival benefits of surgery in these patients.Methods: Patients with early-stage SPLC after SCLC were identified from the Surveillance, Epidemiology, and End Results database. Patients were balanced with propensity score matching (PSM). Overall survival (OS) and lung cancer-specific survival (CSS) were compared between non-surgery group and surgery group with the Kaplan–Meier method and Cox multivariate regressions.Results: A total of 228 patients with early-stage SPLC after SCLC were identified. Surgery was associated with significantly improved OS and CSS in the multivariate Cox regression analysis (OS, 5-year survival: 41.2 vs. 11.6%, HR: 0.42, 95% CI: 0.31–0.59, P < 0.01; CSS, 5-year survival: 46.8 vs. 24.3%, HR: 0.53, 95% CI: 0.37–0.75, P < 0.01). However, no statistically significant survival difference was found between sublobar resection and lobectomy (OS, 5-year survival: 41.0 vs. 45.3%, P = 0.73; CSS, 5-year survival: 43.5 vs. 54.1%, P = 0.49). After 1:1 PSM, 162 patients were selected for further analysis, and surgery continued to demonstrate superior survival (OS, 5-year survival: 44.2 vs. 7.2%, HR: 0.48, 95% CI: 0.33–0.70, P < 0.01; CSS, 5-year survival: 48.0 vs. 20.6%, HR: 0.44, 95% CI: 0.42–0.97, P = 0.03).Conclusion: The resection of early-stage SPLC after SCLC led to significantly improved OS and CSS and therefore should be considered whenever possible. Nevertheless, further randomized controlled trials are warranted to investigate the safety and effect of surgery in these patients.

PURPOSE:We aimed to compare the clinical effectiveness of combination therapy of transarterial chemoembolization (TACE) and microwave ablation (MWA) with TACE monotherapy in BCLC stage B HCC patients with tumor size ≤7 cm and tumor number ≤5.METHODS:We retrospectively reviewed 150 BCLC stage B HCC patients who had received TACE monotherapy or TACE-MWA combination therapy in our hospital from March 2007 to April 2016. The patients were matched by propensity score at the ratio of 1:2 by optimal method. The median follow-up period was 16 months. The overall survival, tumor response and progression-free survival were compared between the two groups by Kaplan–Meier method and Log rank test.RESULTS:Tumor response (complete or partial response or stable disease) rates at 6, 12, 18, 24 months were 55.5%, 37.3%, 21.3%, 15.8% for TACE group, and 74%, 47.8%, 35%, 31.8% for TACE-MWA group, respectively. The survival rates at 1, 3, 5 years were 77.5%, 42.1%, 21% for TACE group and 93.1%, 79%, 67.7% for TACE-MWA group, respectively. Compared with TACE group, the TACE-MWA group had significantly improved progression-free survival (P = 0.044) and overall survival (P = 0.002).CONCLUSION:TACE-MWA combination therapy has better clinical effectiveness than TACE monotherapy in BCLC stage B patients with tumor size ≤7 cm and tumor number ≤5.

Objective: The purpose of this study was to evaluate the diagnostic efficiency of combining plasma microRNAs (miRNAs) and computed tomography (CT) features in the diagnosis of pulmonary nodules.Methods: Ninety-two pulmonary nodule patients who had undergone surgery were enrolled in our study from July 2016 to March 2018 at the Sun Yat-sen University Cancer Center. A prediction model was established by combining 3 miRNAs (miRNA-146a, -200b, and -7) and CT features to identify the pulmonary nodules of these patients. We evaluated the diagnostic performance of this prediction model for pulmonary nodules using the Receiver Operating Characteristic (ROC) curve.Results: The expression levels of miRNA-146a, -200b, and -7 in early-stage non-small cell lung cancer (NSCLC) patients are significantly higher than those in benign nodule patients. We used these three miRNAs and CT features (pleural indentation and speculation) to establish a prediction model for early-stage NSCLC, with a sensitivity and specificity of 92.9%, 83.3% in the training set, respectively. For the validation process, with the sensitivity of 71.8% and the specificity of 69.2%. For ROC curve analyses, area under the curve (AUC) for tumor identification in the training stage and validation stage were 0.929 and 0.781, respectively.Conclusion: Plasma miRNA-146a, miRNA-200b, and miRNA-7 may be potential biomarkers for the early diagnosis of lung cancer. Our prediction model can help to identify the nature of pulmonary nodules with a relatively high diagnostic efficiency.

Background: To investigate the prognostic impact of different types of lymphadenectomy with different extents of tumor resection on the outcomes of stage I non-small-cell lung cancer (NSCLC).Methods: Patients were classified into lobectomy and sublobectomy groups, and then each group was subdivided according to the types of lymphadenectomy. The end points of the study were overall survival (OS) and disease-free survival (DFS). Propensity score matched (PSM) comparative analysis and univariate and multivariate Cox regression analyses were performed.Result: A total of 1,336 patients were included in the current study. Lobectomy was associated with better OS and DFS. In the lobectomy group, lobectomy with bilateral mediastinal lymphadenectomy (BML) was associated with better OS than lobectomy with systematic nodal dissection (SND) or lobe-specific systematic node dissection (L-SND). Lobectomy with SND or L-SND was associated with better OS than lobectomy with systematic nodal sampling (SNS) or selected lymph node biopsy (SLNB). Additionally, lobectomy with BML or SND was associated with better DFS than lobectomy with L-SND or SNS or SLNB. After PSM, compared with lobectomy with SNS or SLNB, lobectomy with SND resulted in more favorable OS and DFS. There was no survival difference between different types of lymphadenectomy for patients who underwent sublobectomy. A multivariable analysis revealed independent associations of lobectomy with BML or SND with better OS and DFS compared with those of lobectomy with SNS or SLNB.Conclusion: This study reveals an association of lobectomy with more systematic and complete lymph node dissection, such as BML or SND, with better prognosis in stage I NSCLC patients.