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Lung cancer is one of the most lethal cancers with high incidence worldwide. The prevention of lung cancer is of great significance to reducing the social harm caused by this disease. An in-depth understanding of the molecular changes underlying precancerous lesions is essential for the targeted chemoprevention against lung cancer. Here, we discovered an increased NQO1 level over time within pulmonary premalignant lesions in both the Kras G12D -driven and nicotine-derived nitrosamine ketone (NNK)-induced mouse models of lung cancer, as well as in Kras G12D -driven and NNK-induced malignant transformed human bronchial epithelial cells (BEAS-2B and 16HBE). This suggests a potential correlation between the NQO1 expression and lung carcinogenesis. Based on this finding, we utilized β-Lapachone (β-Lap), an NQO1 bioactivatable drug, to suppress lung tumorigenesis. In this study, the efficacy and safety of low-dose β-Lap were demonstrated in preventing lung tumorigenesis in vivo. In conclusion, our study suggests that long-term consumption of low-dose β-Lap could potentially be an effective therapeutic strategy for the prevention of lung premalignant lesions. However, further studies and clinical trials are necessary to validate our findings, determine the safety of long-term β-Lap usage in humans, and promote the use of β-Lap in high-risk populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rapid and accurate detection of rare circulating tumor cells (CTCs) in human blood still remains a challenge. We present a surface enhanced Raman spectroscopy (SERS) method based on aptamer-SERS bio-probe recognition coupled with micropore membrane filtration capture for the detection of CTCs at single cell level. The parylene micropore membrane with optimized micropore size installed on a filtration holder could capture bio-probe labeled CTCs by gravity in less than 10 s, and only with very less white blood cells (WBCs) residual. In order to facilitate the synthesis of the aptamer-SERS bio-probe, ethyl acetate dehydration method was established. The bio-probe can be rapidly synthesized within 2 h by binding SH-aptamer to 4- mercaptobenzoic acid (4-MBA) modified AuNPs with the help of ethyl acetate. The SERS bio-probe with selected specific aptamer could distinguish single human non-small cell lung cancer A549 cells from residual WBCs on membrane efficiently and reliably based on their Raman signal intensity difference at 1075 cm -1 . Through the filter membrane coupled with aptamer-SERS bio-probe system, even 20 A549 cells in blood solution simulating CTCs sample can be detected, which the recovery rate and recognition rate are more than 90%. This method is rapid, reliable and cost-effective, which indicates a good prospect in clinical application for CTCs detection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Cancer case during pregnancy is rare, but it is the second leading cause of maternal mortality., Case Presentation: A-32-year old pregnant woman with a gestational age of 37 weeks was admitted to the hospital due to repeated coughing for 5 months. She received Veno-Venous Extracorporeal Membrane Oxygenation (V-V ECMO) treatment for severe hypoxemia after delivery. She was diagnosed with non-small cell lung cancer (NSCLC) with bone metastasis and pneumocystis pneumonia (PCP). She subsequently received anti-tumor therapy and anti-infective therapy. After treatment, her condition improved and she was weaned from ECMO. Two weeks after weaning ECMO, her condition worsened again. Her family chose palliative treatment, and she ultimately died., Conclusions: NSCLC is rare during pregnancy. At present, there is still a lack of standardized methods to manage these cases. For theses cases, the clinician should be wary of opportunistic infections, such as pneumocystis jirovecii (P. jirovecii) and Elizabethkingia spp. Specialized medical teams with abundant experience and multidisciplinary discussions from the perspectives of the patient's clinical characteristics as well as preferences are crucial for developing individualized and the best approach., (© 2023. The Author(s).)

Recently, evidence has shown that microRNA-100-3p (miR-100-3p) has been revealed as a tumor suppressor in diverse human diseases, while its capability in lung cancer warrants further validation. In this work, we aimed to discuss the impact of sevoflurane on biological functions of lung cancer cells by modulating the miR-100-3p/sterol O-acyltransferase 1 (SOAT1) axis. Lung cancer cell lines (A549 and H460) were treated with various concentrations of sevoflurane. Cell viability, proliferation, migration, and invasion were evaluated using MTT, colony formation, wound healing, and transwell assays. Moreover, miR-100-3p and SOAT1 expressions were evaluated by reverse transcription-quantitative polymerase chain reaction in lung cancer cells. The target interaction between miR-100-3p and SOAT1 was predicted by bioinformatics analysis and verified by the dual-luciferase reporter gene assay. The findings of our work demonstrated that sevoflurane impeded the abilities on viability, proliferation, migration, and invasion of A549 and H460 cells. The expression of miR-100-3p was reduced, and SOAT1 expression was elevated in lung cancer cells. miR-100-3p targeted SOAT1. Besides, sevoflurane could lead to expressed improvement of miR-100-3p or limitation of SOAT1. Downregulation of miR-100-3p or upregulation of SOAT1 restored the suppression of sevoflurane on abilities of viability, proliferation, migration, and invasion in A549 and H460 cells. In the rescue experiment, downregulation of SOAT1 reversed the impacts of downregulation of miR-100-3p on sevoflurane on lung cancer cells. Collectively, our study provides evidence that sevoflurane restrained the proliferation and invasion in lung cancer cells by modulating the miR-100-3p/SOAT1 axis. This article provides a new idea for further study of the pathogenesis of lung cancer., Competing Interests: None

As a member of the insulin-receptor superfamily, ALK plays an important role in regulating the growth, proliferation, and survival of cells. ROS1 is highly homologous with ALK, and can also regulate normal physiological activities of cells. The overexpression of both is closely related to the development and metastasis of tumors. Therefore, ALK and ROS1 may serve as important therapeutic targets in non-small cell lung cancer (NSCLC). Clinically, many ALK inhibitors have shown powerful therapeutic efficacy in ALK and ROS1-positive NSCLC patients. However, after some time, patients inevitably develop drug resistance, leading to treatment failure. There are no significant drug breakthroughs in solving the problem of drug-resistant mutations. In this review, we summarize the chemical structural features of several novel dual ALK/ROS1 inhibitors, their inhibitory effect on ALK and ROS1 kinases, and future treatment strategies for patients with ALK and ROS1 inhibitor-resistant mutations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Objectives: Evidence of oral microbiota perturbations has been accumulated for lung cancers. This review focused on the oral microbiota alterations in population suffering from lung cancer. In addition, we also discussed conflicting data about the association between oral microbiota dysbiosis and risk of lung cancer., Methods: A systematic search was conducted in Medline, Embase, PubMed, and Cochrane Library databases. The studies evaluated diversity and abundance of oral microbes in healthy and lung cancer individuals as well as association of periodontal disease and pathogens with lung cancer. Of 3559 studies, 28 included studies were performed in qualitative analysis, and 25 studies were used in meta-analyses for quantitative assessment. Heterogeneity was analyzed by using I² and chi-squared Q test statistics. Statistical analyses were performed by using the RevMan 5.4 software., Results: Compared with the control, lung cancer patients had lower alpha diversity (Shannon: SMD = -0.54; 95% CI, -0.90 to -0.19; P < .01, I 2  = 71%). In nested case-control studies, individuals with decreased alpha diversity tended to have an increased risk of lung cancer (observed species: HR = 0.90; 95% CI, 0.85-0.96; P < .01, I 2  = 0%; Shannon: HR = 0.89; 95% CI, 0.83-0.95; P < .01, I 2  = 0%). Overall, no strong evidence of association of relative abundance with specific oral microbes with lung cancers was found because of inconsistent data. No associations were found between periodontal pathogens and lung cancer risk (red complex: HR = 1.12, 95% CI: 0.42-3.02, P = .82, I 2  = 62%; orange complex: HR =1.77, 95% CI: 0.78-3.98, P = .17, I 2  = 36%), expect for Fusobacterium nucleatum (HR = 2.27, 95% CI: 1.13-4.58, P = .02, I 2  = 0%). The positive association of periodontal disease with lung cancer risk was found (HR = 1.58, 95% CI: 1.25-2.00, P < .001, I 2 = 0%) with increase of periodontal diseases severity (HR = 2.39, 95% CI: 1.57-3.66, P < .001, I 2  = 0%). However, such association was not found in never-smoker participants (HR = 1.00, 95% CI: 0.76-1.31, P = .37, I 2 = 7%)., Conclusions: Lower alpha diversity of oral microbiome may be associated with a greater risk of lung cancer and might serve as a predictive signal of lung cancer risk. There was no strong evidence of relative abundance of oral microbial taxa and periodontal pathogens in lung cancer patients. Fusobacterium nucleatum might be a potential microbial candidate of biomarkers in lung cancer. Periodontal disease may be positively associated with lung cancer risk by confounding of smoking, but not an independent risk factor., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The effect of various metastases patterns on the prognosis of lung adenocarcinoma (AD) remains unknown. The purpose of our retrospective study is to determine whether various metastases patterns have a prognostic impact on patients with organ metastatic lung AD. Patient data was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier method was chosen for the evaluation of overall survival (OS) rate. Univariable and multivariable Cox regression analyses were conducted to evaluate independent prognostic factors. In the SEER database, 12,228 patients with IV lung AD were retrieved in total. And 78.78% of those patients (9633/12,228) suffered from one of brain, lung, liver or bone metastasis due to disease progression. It was found that the most common site in patients with metastatic lung AD was brain (21.20%), and the least common site of metastasis was liver (3.50%). Patients who suffered single lung metastatic showed relatively good OS, and the median survival time was 11 months (95% CI 0.470-0.516). For those with 2 metastatic sites, data analysis suggested that the median survival times of patients with bone and lung metastasis (10 months; 95% CI 0.469-0.542) were better than others. For those with 3 metastatic sites, data analysis suggested that metastatic pattern had no effect on the OS. Brain is the most common single metastasis site of lung AD. Compared with the other 3 metastatic sites, patients with lung metastasis had better survival results. Deeper knowledge of metastatic patterns will help doctors to better understand the prognosis and formulate more appropriate treatment plans., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Cancer cachexia is a deadly wasting syndrome that accompanies various diseases (including ~ 50% of cancers). Clinical studies have established that cachexia is not a nutritional deficiency and is linked to expression of certain proteins (e.g., interleukin-6 and C-reactive protein), but much remains unknown about this often fatal syndrome., Methods: First, cachexia was created in experimental mouse models of lung cancer. Samples of human lung cancer were used to identify the association between the serum lipocalin 2 (LCN2) level and cachexia progression. Then, mouse models with LCN2 blockade or LCN2 overexpression were used to ascertain the role of LCN2 upon ferroptosis and cachexia. Furthermore, antibody depletion of tissue-infiltrating neutrophils (TI-Neu), as well as myeloid-specific-knockout of Lcn2, were undertaken to reveal if LCN2 secreted by TI-Neu caused cachexia. Finally, chemical inhibition of ferroptosis was conducted to illustrate the effect of ferroptosis upon tissue wasting., Results: Protein expression of LCN2 was higher in the wasting adipose tissue and muscle tissues of experimental mouse models of lung cancer cachexia. Moreover, evaluation of lung cancer patients revealed an association between the serum LCN2 level and cachexia progression. Inhibition of LCN2 expression reduced cachexia symptoms significantly and inhibited tissue wasting in vivo. Strikingly, we discovered a significant increase in the number of TI-Neu in wasting tissues, and that these innate immune cells secreted high levels of LCN2. Antibody depletion of TI-Neu, as well as myeloid-specific-knockout of Lcn2, prevented ferroptosis and tissue wasting in experimental models of lung cancer cachexia. Chemical inhibition of ferroptosis alleviated tissue wasting significantly and also prolonged the survival of cachectic mice., Conclusions: Our study provides new insights into how LCN2-induced ferroptosis functionally impacts tissue wasting. We identified LCN2 as a potential target in the treatment of cancer cachexia., (© 2023. The Author(s).)

Non-small cell lung cancer (NSCLC) is the predominant form of lung cancer and is one of the most fatal cancers worldwide. Recently, the International Association for the Study of Lung Cancer (IASLC) proposed a novel grading system based on the predominant and high-grade histological patterns for invasive pulmonary adenocarcinoma (IPA). To improve outcomes for NSCLC patients, we combined serum metabolomics and fecal microbiology to screen biomarkers in patients with early-stage NSCLC and identified characteristic microbial profiles in patients with different grades of IPA. 26 genera and 123 metabolites were significantly altered in the early-stage NSCLC patients. Agathobacter , Blautia , Clostridium , and Muribaculacea were more abundant in the early-stage NSCLC patients compared with healthy controls. For the different grades of IPA, the characteristic microorganisms are as follows: Blautia and Marinobacter in IPA grade type 1; Dorea in IPA grade type 2; and Agathobacter in IPA grade type 3. In the metabolome results, the early-stage NSCLC group mainly included higher levels of sphingolipids (D-erythro-sphingosine 1-phosphate, palmitoyl sphingomyelin), fatty acyl (Avocadyne 1-acetate, 12(S)-HETE, 20-Carboxy-Leukotriene B4, Thromboxane B3, 6-Keto-prostaglandin f1alpha, Sebacic acid, Tetradecanedioic acid) and glycerophospholipids (LPC 20:2, LPC 18:0, LPC 18:4, LPE 20:2, LPC 20:1, LPC 16:1, LPC 20:0, LPA 18:2, LPC 17:1, LPC 17:2, LPC 19:0). Dysregulation of pathways, such as sphingolipid metabolism and sphingolipid signaling pathway may become an emerging therapeutic strategy for early-NSCLC. Correlation analysis showed that gut microbiota and serum metabolic profiles were closely related, while Muribaculacea and Clostridium were the core genera. These findings provide new biomarkers for the diagnosis of early-stage NSCLC and the precise grading assessment of prognostic-related IPAs, which are of clinical importance and warrant further investigation of the underlying molecular mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ni, Kong, Yan, Fu, Zhou and Xu.)

Background: This study compares the short- and long-term outcomes of open vs robotic vs video-assisted thoracoscopic surgery (VATS) lobectomy for stage II-IIIA non-small-cell lung cancer (NSCLC)., Methods: Outcomes of patients with stage II-IIIA NSCLC (excluding T4 tumors) who received open and minimally invasive surgery (MIS) lobectomy in the National Cancer Database from 2010 to 2017 were assessed using propensity score-matched analysis., Results: A propensity score-matched analysis of 4652 open and 4652 MIS patients demonstrated a decreased median length of stay associated with MIS compared with open lobectomy (5 vs 6 days; P < .001). There were no significant differences in 30-day mortality, 30-day readmission, or overall survival between the open and MIS groups. A propensity score-matched analysis of 1186 VATS and 1186 robotic patients showed that compared with VATS, the robotic approach was associated with no significant differences in 30-day mortality, 30-day readmission, and overall survival. However, the robotic group had a decreased median length of stay compared with VATS (4 vs 5 days; P < .001). The conversion rate was also significantly lower for robotic compared with VATS lobectomy (8.9% vs 15.9%, P < .001)., Conclusions: No significant differences were found in long-term survival between open and MIS lobectomy and between VATS and robotic lobectomy for stage II-IIIA NSCLC. However, the MIS approach was associated with a decreased length of stay compared with the open approach. The robotic approach was associated with decreased length of stay and decreased conversion rate compared with the VATS approach., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Recombinant human granulocyte colony-stimulating factor (rhG-CSF) reduces neutropenia events and is widely used in cancer patients receiving chemotherapy. However, the effects of rhG-CSF on distant organ metastasis (DOM) in non-small-cell lung cancer (NSCLC) patients following postoperative chemotherapy are not clear., Methods: A retrospective cohort study was performed on NSCLC patients who underwent complete surgical resection and postoperative systemic chemotherapy at The First Affiliated Hospital of Nanchang University between 1 January 2012 and 31 December 2017. The effect of rhG-CSF on DOM was assessed with other confounding factors using Cox regression analyses., Results: We identified 307 NSCLC patients who received postoperative systemic chemotherapy (n = 246 in the rhG-CSF group, n = 61 in the No rhG-CSF group). The incidence of DOM in postoperative NSCLC patients with rhG-CSF treatment was observably higher than in patients without rhG-CSF treatment (48.3% vs. 27.9%, p < 0.05). Univariate regression analysis revealed that rhG-CSF and pathological stage were independent risk factors for metastasis-free survival (MFS) (p < 0.05). RhG-CSF users had a higher risk of DOM (adjusted HR: 2.33, 95% CI: 1.31-4.15) than nonusers of rhG-CSF. The association between rhG-CSF and the risk of DOM was significant only in patients presenting with myelosuppression (HR: 3.34, 95% CI: 1.86-6.02) and not in patients without myelosuppression (HR: 0.71, 95% CI: 0.17-2.94, Interaction p-value< 0.01). The risk increased with higher dose density of rhG-CSF compared to rhG-CSF versus no users (p for trend< 0.001)., Conclusion: These analyses indicate that rhG-CSF use is related to DOM following postoperative chemotherapy in NSCLC., (© 2022. The Author(s).)

Therapeutic tumor vaccines have become an important breakthrough in the treatment of various solid tumors including lung cancer. Dendritic cells (DCs)-based tumor vaccines targeting tumor-associated antigens (TAAs) play a key role in immunotherapy and immunoprevention. However, the weak immunogenicity of TAAs and low immune response rates are a major challenge faced in the application of therapeutic tumor vaccines. Here, we tested whether targeting an attractive target Mesothelin (MSLN) and PD-L1 immune checkpoint molecule to DCs in vivo would elicit therapeutic antitumor cytotoxic T lymphocyte (CTL) response. We generated specific MSLN fragment combined with PD-L1 and GM-CSF peptide immunogen (MSLN-PDL1-GMCSF) based on the novel anti-PD-L1 vaccination strategy we recently developed for the cancer treatment and prevention. We found that DCs loaded with MSLN-PDL1-GMCSF vaccine elicited much stronger endogenous anti-PD-L1 antibody and T cell responses in immunized mice and that antigen specific CTLs had cytolytic activities against tumor cells expressing both MSLN and PD-L1. We demonstrated that vaccination with MSLN-PDL1-GMCSF potently inhibited the tumor growth of MSLN + and PD-L1 + lung cancer cells, exhibiting a significant therapeutic anti-tumor potential. Furthermore, PD-1 blockade further improved the synergistic antitumor therapeutic efficacy of MSLN-PDL1-GMCSF vaccine in immunized mice. In summary, our data demonstrated for the first time that this PD-L1-containing MSLN therapeutic vaccine can induce persistent anti-PD-L1 antibody and CTL responses, providing an effective immunotherapeutic strategy for lung cancer immunotherapy by combining MSLN-PDL1-GMCSF vaccine and PD-1 blockade., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zeng, Pan, Fang, Jia, Zhang, He, Zhong, He, Yang, Shi, Zhong, Zeng, Fu, Huang and Liu.)

The higher immunogenicity of tumors usually predicts favorable therapeutic responses. Tumor antigens dominate the immunogenic character within tumors. We investigated if there was a targetable tumor antigen during immunogenic chemotherapy within lung cancer. Chemotherapy-induced immunogenic senescence was demonstrated using a multi-marker, three-step workflow, and RNA-sequencing data. The ability of anti-lung-specific X protein (LUNX) antibody to suppress the survival of senescent lung cancer cells was evaluated in vitro and in vivo using real-time cytotoxicity analysis and xenograft mouse models, respectively. The induction of cellular senescence by immunogenic chemotherapy boosted cell-surface shuttling of LUNX and enhanced the immunogenic features of senescent tumor cells, which sensitized lung cancer cells to anti-LUNX antibody-mediated therapy and contributed to tumor suppression. The immunogenic senescence-mediated anti-tumor response was triggered by the direct action of antibody on tumor cells, strengthened by natural-killer cells through an antibody-dependent cell-mediated cytotoxicity response, and ultimately, led to tumor control. Our findings suggest that LUNX is a lung cancer targetable-immunogenic antigen. The proportion of lung cancers responding to LUNX-targeting therapy could be expanded substantially by immunogenic chemotherapy that induces senescence-associated translocation of LUNX to the plasma membrane., (© 2021. The Author(s).)

Neutrophil extracellular traps (NETs) that are produced in the tumour microenvironment (TME) have been suggested to play an essential role in the dissemination of metastatic cancer under multiple infectious and inflammatory conditions. However, the functions of NETs in promoting non-small cell lung cancer (NSCLC) metastasis and the underlying mechanisms remain incompletely understood. Here, we found that NETs promoted NSCLC cell invasion and migration by inducing epithelial to mesenchymal transition (EMT). To explore how NETs contribute to NSCLC metastasis, microarrays were performed to identify substantial numbers of long noncoding RNAs (lncRNAs) and mRNAs that were differentially expressed in NSCLC cells after stimulation with NETs. Interestingly, we observed that the expression of lncRNA MIR503HG was downregulated after NETs stimulation, and ectopic MIR503HG expression reversed the metastasis-promoting effect of NETs in vitro and in vivo . Notably, bioinformatics analysis revealed that differentially expressed genes were involved in the NOD-like receptor and NF-κB signalling pathways that are associated with inflammation. NETs facilitated EMT and thereby contributed to NSCLC metastasis by activating the NF-κB/NOD-like receptor protein 3 (NLRP3) signalling pathway. Further studies revealed that MIR503HG inhibited NETs-triggered NSCLC cell metastasis in an NF-κB/NLRP3-dependent manner, as overexpression of NF-κB or NLRP3 impaired the suppressive effect of MIR503HG on NETs-induced cancer cell metastasis. Together, these results show that NETs activate the NF-κB/NLRP3 pathway by downregulating MIR503HG expression to promote EMT and NSCLC metastasis. Targeting the formation of NETs may be a novel therapeutic strategy for treating NSCLC metastasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Liu, Chen, Fang, Li, Yuan, Qian, Yin, Yu, Fu, Zhang and Li.)

Background: He-Chan Pian (HCP), a traditional Chinese medicinal formula, shows promising efficacy for the treatment of lung cancer., Purpose: Gremlin (GREM1) plays an important role in gastrointestinal tumor metastasis; however, little is known about its role in lung cancer. We determined the mechanism underlying the protective effect of HCP against metastasis in a mouse model of non-small cell lung cancer (NSCLC) and demonstrated the role of GREM1., Methods: Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was used to analyze the herbal components and metabolites from the serum of HCP-treated mice. The tumor, liver, and kidney were examined histologically, and the antitumor effects and toxicity of HCP were evaluated. Levels of epithelial-mesenchymal transition (EMT)-associated transcription factors were measured using western blotting in tumors from five groups (i.e., model, HCP [L], HCP [M], HCP [H], and positive control [cisplatin, DDP]). Differentially expressed proteins and genes were identified using protein chip and sequencing analyzes, respectively. Short hairpin RNAs and overexpression plasmids were introduced into cells to evaluate the effects of GREM1. To evaluate proliferation, migration, and invasion, the expression levels of proteins involved in the Rap1 pathway and EMT were measured in vitro. Xenograft tumors with overexpression-GREM1 (OE-GREM1) in A549 cells were examined for cell proliferation. A dual-luciferase assay was performed to verify the direct interaction of GREM1 with miR-205-5p in lung cancer., Results: Thirty-six ingredients and bioactive constituents detected in the serum of HCP-treated mice were identified as the key compounds involved in the inhibition of tumor growth. Animal experiments revealed that HCP significantly decreased tumor volumes and had no adverse effects on the liver or kidney or side effects. GREM1 upregulation was closely related to tumor metastasis and was regulated by miR-205-5p, as confirmed using a dual-luciferase reporter assay. OE-GREM1 promoted A549 cell migration and invasion, promoted EMT, and increased the expression of Rap1 pathway intermediaries, whereas shGREM1 had the opposite effects. Furthermore, the effects of OE-GREM1 on proliferation in the A549 xenograft mouse model were attenuated, although HCP has an inhibitory effect on tumors., Conclusion: Our results suggest that HCP contributes to the inhibition of NSCLC metastasis via the Gremlin/Rap1 signaling pathway regulated by miR-205-5p., (Copyright © 2021. Published by Elsevier GmbH.)

Background: The interaction between tumor cells and tumor microenvironment is a necessary condition for promoting the metastasis of malignant tumors., Methods: Two different transwell culture systems were interfered with by recombinant factor placental growth factor (re-PIGF) and the re-PIGF + transforming growth factor-β1 (TGF-β1)-neutralizing antibody (anti-TGF-β1). We performed immunofluorescence, flow cytometry and enzyme linked immunosorbent assay (ELISA) to analyze the expression of PIGF, fms-like tyrosine kinase-1 (Flt-1), macrophage marker F4/80 + , macrophage M2 marker CD163 + and TGF-β1 in vitro. Meanwhile, cell viability assay and optical microscope assay were conducted to explore the cell viability and vascularization ability of human umbilical vein endothelial cells (HUVECs)., Results: Re-PIGF increased the expression of PIGF in A549 cells and the expression of Flt-1 in BM-Mac cells, and significantly enhanced the ability of bone marrow-derived macrophages (BM-Mac) to transform into macrophages. At the same time, re-PIGF increased the expression of cytokine TGF-β1 in A549 cells/BM-Mac transwell culture system. On the contrary, re-PIGF + anti-TGF-β1 inhibited the expression of Flt-1 in BM-Mac cells and inhibited the ability of BM-Mac cells to transform into macrophages. Finally, re-PIGF + anti-TGF-β1 reduced the cell viability and angiogenesis of HUVECs., Conclusion: The surface molecule PIGF of lung cancer cells could bind to the receptor Flt-1 on the surface of macrophages, thereby increasing the production of TGF-β1, and ultimately promoting the formation of angiogenesis in lung cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Circular RNAs (circRNAs) have recently been described as key regulators in the progression of non-small cell lung cancer (NSCLC), and this study aimed to investigate the functional role of circMAT2B in NSCLC. CircMAT2B expression in NSCLC tissues and cell lines was investigated using RT-qPCR analysis. A series of functional experiments, including MTT assay, colony formation assay, wound healing assay and transwell assay, were carried out to investigate the effects of circMAT2B knockdown/overexpression on the malignant traits of NSCLC cells. Western blot analysis was performed to detect the expression of EMT-related proteins. Dual-luciferase reporter assay and RIP assay were further carried out to analyze the interaction between circMAT2B and miR-431 in NSCLC. We observed that circMAT2B was overexpressed in NSCLC tissues and cell lines, and high expression of circMAT2B was closely associated with large tumor size, advanced TNM stage and poor prognosis of NSCLC patients. Further functional experiments showed that circMAT2B knockdown markedly inhibited the proliferation, migration, invasion and EMT of NSCLC cells, whereas circMAT2B overexpression led to the opposing results. Mechanistically, circMAT2B could directly interact with miR-431, and subsequently decrease miR-431 expression in NSCLC. The effects of circMAT2B overexpression in NSCLC cells were abrogated by miR-431 restoration. Our findings revealed the novel oncogenic roles of circMAT2B in NSCLC by sponging miR-431.

Radiotherapy plays an essential role in the treatment of non-small-cell lung cancer (NSCLC). However, cancer cells' resistance to ionizing radiation (IR) is the primary reason for radiotherapy failure leading to tumor relapse and metastasis. DNA double-strand breaks (DSB) repair after IR is the primary mechanism of radiotherapy resistance. In this study, we investigated the effects of autophagy-inducing agent, Rapamycin (RAPA), combined with the histone deacetylase inhibitor (HDACi), Suberoylanilide Hydroxamic Acid (SAHA), on the radiosensitivity of A549 and SK-MES-1 cells, and examined the combination effects on DNA damage repair, and determined the level of autophagy and acetylation in A549 cells. We also investigated the combination treatment effect on the growth of A549 xenografts after radiotherapy, and the level of DNA damage, autophagy, and acetylation. Our results showed that RAPA combined with SAHA significantly increased the inhibitory effect of radiotherapy compared with the single treatment group. The combined treatment increased the expression of DNA damage protein γ-H2AX and decreased DNA damage repair protein expression. RAPA combined with SAHA was induced mainly by regulating acetylation levels and autophagy. The effect of combined treatment to increase radiotherapy sensitivity will be weakened by inhibiting the level of autophagy. Besides, the combined treatment also showed a significantly inhibited tumor growth in the A549 xenograft model. In conclusion, these results identify a potential therapeutic strategy of RAPA combined with SAHA as a radiosensitizer to decreased DSB repair and enhanced DNA damage by inducing acetylation levels and autophagy for NSCLC.

Neutrophil extracellular traps (NETs) are closely related to cancer progression. NETs-related lncRNAs play crucial roles in non-small-cell lung cancer (NSCLC) but there have been no systematic studies regarding NETs-related long noncoding RNA (lncRNA) signatures to forecast the prognosis of NSCLC patients. It's essential to build commensurate NETs-related lncRNA signatures. The expression profiles of prognostic mRNAs and lncRNAs and relevant clinical data of NSCLC patients were downloaded from The Cancer Genome Atlas (TCGA) database. The NETs-related genes came from the results of our transcriptome RNA microarray data. The co-expression network of lncRNAs and NETs-related genes was structured to confirm NETs-related lncRNAs. The 19 lncRNAs correlated with overall survival (OS) were selected by exploiting univariate Cox regression ( P < 0.05). Lasso regression and multivariate Cox regression ( P < 0.05) were utilized to develop a 12-NETs-related lncRNA signature. We established a risk score based on the signature, which suggested that patients in the high-risk group displayed significantly shorter OS than patients in the low-risk group ( P < 0.0001, P = 0.0023 respectively in the two cohorts). The risk score worked as an independent predictive factor for OS in both univariate and multivariate Cox regression analyses (HR> 1, P < 0.001). Additionally, by RT-qPCR, we confirmed that NSCLC cell lines have higher levels of the three adverse prognostic NETs-related lncRNAs than normal lung cells. The expression of lncRNAs significantly increases after NETs stimulation. In short, the 12 NETs-related lncRNAs and their model could play effective roles as molecular markers in predicting survival for NSCLC patients.

Molecules involved in crosstalk between tumor cells and fibroblasts play vital roles in tumor progression. Extracellular matrix proteins, whose abundance is altered after being affected by tumor-derived exosomes, possess considerable promise as biomarkers for diagnosis or prognosis. In this study, quantitative proteomics is employed to determine the abundance of proteins secreted by normal fibroblasts and exosome-activated fibroblasts, which first identify differentially secreted proteins affected by lung cancer cell-derived exosomes. Based on the differentially secreted proteins and multiple independent datasets comprising 1897 patient samples with non-small cell lung carcinoma or other lung diseases, a diagnostic marker is identified that can effectively distinguish tumor tissues from normal tissue, as well as tumor-associated stroma from normal stroma, and a five-gene prognostic signature is presented with independent prognostic impact to identify patients who may require further adjuvant therapy after surgical resection. In addition, the secretome provides novel potential targets for clinical treatment., (© 2020 Wiley-VCH GmbH.)

Immunogenic chemotherapy has been shown to be effective against several cancer types. Here, we identified trametinib as an inducer of immunogenic cell death (ICD), and found that it exerts beneficial antitumor effects if used in combination with interleukin (IL)-12 in a Kras-mutant mouse model of spontaneous lung cancer. Tumor cells treated with trametinib showed the hallmarks of ICD, including cell-surface expression of calreticulin, release of high mobility group box 1 (HMGB1) from the nucleus, and activation of dendritic cells. Tumor-bearing mice treated with both trametinib and IL-12 showed increased infiltration and proliferation of T cells within the tumor, as well as increased effector function of NK cells and T cells, indicating that this therapeutic combination can improve the quality of the immune response. Taken together, our results provide a potential new therapeutic regimen for the treatment of KRAS-mutant lung adenocarcinomas., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To investigate the effective dose (E) and convolution kernel's effects on the detection of pulmonary nodules in different artificial intelligence (AI) software systems., Methods: Simulated nodules of various sizes and densities in the Lungman phantom were CT scanned at different levels of E (3 - 5, 1 - 3, 0.5 - 1, and <0.5 mSv) and were reconstructed with different kernels (B30f, B60f, and B80f). The number of nodules and corresponding volumes in different images were detected by four AI software systems (A, B, C, and D). Sensitivity, false positives (FPs), false negatives (FNs), and relative volume error (RVE) were calculated and compared to the aspects of the E and convolution kernel., Results: System B had the highest median sensitivity (100 %). The median FPs of systems B (1) and D (1) was lower than A (11.5) and C (5). System D had the smallest RVE (13.12 %). When the E was <0.5 mSv, system D's sensitivity decreased, while the FPs and FNs of systems A and B increased significantly (P < 0.05). When the kernel was changed from B80f to B30f, the FPs of system A decreased, while that of system C increased, and the RVE of systems A, B, and C increased (P < 0.05)., Conclusion: AI software systems B and D have high detection efficiency under normal or low dose conditions and show better stability. However, the detection efficiency of systems A and C would be affected by the E or convolution kernel, but the E would not affect the volume measurement of four systems., Competing Interests: Declaration of Competing Interest There is no conflict of interest in the submission of this manuscript and all authors are authorized to publish it. All the listed authors approved the manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Circular RNAs (circRNAs) are a novel class of noncoding RNAs that regulate gene expression at the transcriptional or posttranscriptional level. According to recent studies, circRNAs are involved in the pathogenesis of cancer, but the roles of circRNAs in lung adenocarcinoma are largely unknown., Methods: In this study, we identified a novel upregulated circRNA, hsa&#95;circ&#95;0000326, in human lung adenocarcinoma tissues using microarray analysis and qRT-PCR. We then explored the biological role of hsa&#95;circ&#95;0000326 using gain- and loss-of-function assays in adenocarcinoma cells. Bioinformatics databases were used to screen for potential target miRNAs and the luciferase reporter assays and RNA-FISH further validated the interaction. Downstream protein was detected by western blot. Finally, we established xenografts in nude mice to assess the function of hsa&#95;circ&#95;0000326 in vivo., Results: We found that high expression of hsa&#95;circ&#95;0000326 was correlated with tumor size, regional lymph node status and differentiation in human lung adenocarcinoma. Additionally, we conducted gain- and loss-of-function assays and found that hsa&#95;circ&#95;0000326 acted as a positive regulator of cell proliferation and migration and a negative regulator of apoptosis. Mechanistic studies showed that hsa&#95;circ&#95;0000326 acted as a miR-338-3p sponge and altered the function of miR-338-3p, which in turn upregulated the expression of the downstream target RAB14 and affected the proliferation, migration and apoptosis of lung adenocarcinoma cells., Conclusions: Collectively, our study results reveal crucial roles for hsa&#95;circ&#95;0000326 in the proliferation, migration and apoptosis of lung adenocarcinoma cells and suggest that hsa&#95;circ&#95;0000326 may represent a potential therapeutic target in patients with lung adenocarcinoma.

Lung cancer (LC) is one of the malignant tumors with growing morbidity and mortality. The involvement of runt-related transcription factor 1 (RUNX1) in LC patients has been elucidated. We intended to research mechanisms of RUNX1 and tartrate-resistant acid phosphatase 5 (ACP5) in LC. Firstly, ACP5 levels in LC tissues, paracancerous tissues, LC cells and tracheal epithelial cells were detected. RUNX1 overexpression plasmid and interference plasmid were constructed and transfected into 95C cells and A549 cells, respectively. The binding of RUNX1 to ACP5 promoter was tested. Additionally, the gain- and loss-of-function were performed to explore the effects of ACP5 and RUNX1 on LC biological process. The xenograft tumor in nude mice was constructed in vivo to verify in vitro results. Functional rescue experiment was performed by adding MAPK-specific activator P79350 to A549 cells with si-ACP5 to measure the effects of ERK/MAPK axis on LC progression. Consequently, we found ACP5 expression was higher in LC tissues and cells, and ACP5 silencing suppressed LC cell growth. Overexpression of ACP5 promoted malignant biological behavior of LC cells. RUNX1 could bind to ACP5 promoter, and overexpressed RUNX1 promoted ACP5 expression and LC cell growth. Moreover, ACP5 upregulated the ERK/MAPK axis and thus promoted LC progression. The results of xenograft tumor in nude mice showed that silencing ACP5 could inhibit the growth of LC cells in vivo . To conclude, silenced RUNX1 inhibits LC progression through the ERK/MAPK axis by binding to ACP5. This study may provide new approaches for LC treatment.

Natural killer (NK) cells are effector lymphocytes with pivotal roles in the resistance against various tumors; dysfunction of NK cells often results in advanced tumor progression. Tumors develop in three stages comprising initiation, promotion, and progression, but little is known about the interrelationships between NK cells and tumor cells at different stages of tumor development. Here, we demonstrated that NK cells prevented tumor initiation potently but did not prevent tumor promotion or tumor progression in Kras-driven lung cancer. Moreover, loss of the antitumor effect in NK cells was closely associated with their dysfunctional state during tumor promotion and progression. Mechanistically, aberrant fructose-1,6-bisphosphatase (FBP1) expression in NK cells elicited their dysfunction by inhibiting glycolysis and impairing viability. Thus, our results show dynamic alterations of NK cells during tumor development and uncover a novel mechanism involved in NK cell dysfunction, suggesting potential directions for NK cell-based cancer immunotherapy involving FBP1 targeting., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The relationship between O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and clinicopathological characteristics of non-small-cell lung carcinoma (NSCLC) has remained controversial and unclear. Therefore, in this study we have undertaken a systematic review and meta-analysis of relevant studies to quantitatively investigate this association. We identified 30 eligible studies investigating 2714 NSCLC patients. The relationship between MGMT hypermethylation and NSCLC was identified based on 20 studies, including 1539 NSCLC patient tissue and 1052 normal and adjacent tissue samples (OR = 4.60, 95% CI = 3.46~6.11, p < 0.00001). MGMT methylation varied with ethnicity (caucasian: OR = 4.56, 95% CI = 2.63~7.92, p < 0.00001; asian: OR = 5.18, 95% CI = 2.03~13.22, p = 0.0006) and control style (autologous: OR = 4.44, 95% CI = 3.32~5.92, p < 0.00001; heterogeneous: OR = 9.05, 95% CI = 1.79~45.71, p = 0.008). In addition, MGMT methylation was observed to be specifically associated with NSCLC clinical stage, and not with age, sex, smoking, pathological types, and differentiation status. Also MGMT methylation did not impact NSCLC patients survival (HR = 1.32, 95% CI = 0.77~2.28, p = 0.31). Our study provided clear evidence about the association of MGMT hypermethylation with increased risk of NSCLC.

Background: Carina resection and reconstruction is a challenging procedure for thoracic surgeons. We describe a novel technique of thoracoscopic carina reconstruction using the natural bifurcation, following pulmonary resection of the lung neoplasm. To our knowledge, it is the first report of this kind., Case Presentation: A 71-year-old male diagnosed of squamous cell lung cancer received two-port approached video-assisted thoracoscopic right bilobectomy with carina resection after 2 cycles of neoadjuvant therapy. After the removal of right lower lobe and middle lobe, the 7 station lymph nodes were resected with the invaded carina and bronchial walls in an en-bloc fashion. The neocarina was reconstructed by the natural bifurcation between the right upper bronchus and the bronchus intermedius. Intraoperative blood loss was about 220 mL, and operative time was about 225 min. The postoperative course was uneventful. The pathological TNM stage was pT3N2M0, IIIA. Adjuvant chemotherapy using gemcitabine and cisplatin was administered for 4 cycles. Follow-up 6 months after surgery confirmed no stenosis and no signs of local recurrence by bronchoscopy and CT scan., Conclusions: We consider that the surgical procedure described here is a new alternative strategy for carina resection and reconstruction in the similar situation. The minimally invasive method is safe and effective for this challenging operation.

Background: Despite the robotic surgery is widely applied, sleeve lobectomy for lung cancer using the Da Vinci surgical system is still less performed. We described a sleeve lobectomy for adenocarcinoma located at the left lower lobe using the Da Vinci surgical system., Case Presentation: A case of 57-year old female referred to our hospital. Computed tomography scan showed an occupation located at the left lower lobe and adenocarcinoma project from the lobe bronchus was diagnosed by bronchoscope examination. A sleeve lobectomy was performed using the Da Vinci surgical system and the postoperative recovery was uneventful., Conclusions: Robotic thoracic surgery is feasible to perform sleeve lobectomy inspite of inadequate experience.

Purpose: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein associated with several aggressive and advanced cancers. Whether IMP3 can predict invasion, and prognosis in patients with human lung adenocarcinoma (LAC) remains unclear., Methods: Ninety-five LAC and 75 non-tumor lung tissue samples were included in a tissue microarray. IMP3 expression was assessed by immunohistochemical examination. Correlation between IMP3 expression levels, clinicopathological characteristics, and overall prognosis was evaluated. In a separate in vitro study, RNA interference method was applied for knockdown of IMP3 gene in human LAC cell lines. Invasive potential of LAC cells was then evaluated by transwell migration assay., Results: IMP3 immunoreactivity was observed in 39 out of 95 (41.1 %) LAC patients, but not in non-tumor lung tissues. IMP3 expression levels were closely associated with histological grade (P = 0.037), TNM stage (P = 0.034), and lymph node metastasis (P = 0.011). Patients presenting with positive IMP3 expression (P = 0.000), an advanced TNM stage (P = 0.000), and lymph node metastasis (P = 0.001) had a worse overall survival, compared to those lacking these characteristics. Both IMP3 expression (hazard ratio [HR], 2.310; 95 % confidence interval [CI] 1.192-4.476; P = 0.013) and TNM stage (HR 2.338; 95 % CI 1.393-3.925; P = 0.001) were independent predictors of poor prognosis. The invasive potential of LAC cells was significantly inhibited by IMP3 knockdown., Conclusion: IMP3 appears to play an important role in tumor invasion in patients with LAC and may serve as a useful prognostic biomarker in these patients.

There remains a great need for effective therapies for lung cancer, the majority of which are non-small cell lung cancers (NSCLC). Here, we report the identification of a novel candidate therapeutic target, LUNX, as a molecule overexpressed in primary NSCLC and lymph node metastases that is associated with reduced postoperative survival. Functional studies demonstrated that LUNX overexpression promoted lung cancer cell migration and proliferation by interactions with the chaperone protein 14-3-3. Conversely, LUNX silencing disrupted primary tumor growth, local invasion, and metastatic colonization. The finding that LUNX was expressed on cell membranes prompted us to generate and characterize LUNX antibodies as a candidate therapeutic. Anti-LUNX could downregulate LUNX and reduce lung cancer cell proliferation and migration in vitro. Administered in vivo to mice bearing lung cancer xenografts, anti-LUNX could slow tumor growth and metastasis and improve mouse survival. Together, our work provides a preclinical proof of concept for LUNX as a novel candidate target for immunotherapy in lung cancer., (©2015 American Association for Cancer Research.)

To investigate the surgical management of malignant pleural mesothelioma, 2 randomized controlled trials have been completed. We discuss the findings from these trials and the current evidence of various surgical techniques to treat this challenging disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Squamous cell carcinoma (SCC) has a high worldwide incidence that is commonly seen as head and neck cancers, esophageal cancers, and non-small cell lung cancers. There is a poor prognosis for SCC due to potential recurrence and its metastatic tendency so the 5-year survival rate is very low. Target therapy is a novel and promising treatment strategy exhibiting great anti-tumor effects and survival benefits in SCC. This review summarizes current treatment strategies from clinical and experimental studies, including the agents targeting epidermal growth factor receptors, RNA polymerase, toll-like receptors, p38α MAPK, CXCR, and the related combination therapy regimens. However, there are still many challenges we have to face. It is a burning need to improve the development and availability of drug formulations.