Non-small Cell Lung Cancer Progression Research Articles

LAPTM4B counteracts ferroptosis via suppressing the ubiquitin-proteasome degradation of SLC7A11 in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, necessitating the identification of novel therapeutic targets. Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is involved in biological processes critical to cancer progression, such as regulation of solute carrier transporter proteins and metabolic pathways, including mTORC1. However, the metabolic processes governed by LAPTM4B and its role in oncogenesis remain unknown. In this study, we conducted unbiased metabolomic screens to uncover the metabolic landscape regulated by LAPTM4B. We observed common metabolic changes in several knockout cell models suggesting of a role for LAPTM4B in suppressing ferroptosis. Through a series of cell-based assays and animal experiments, we demonstrate that LAPTM4B protects tumor cells from erastin-induced ferroptosis both in vitro and in vivo. Mechanistically, LAPTM4B suppresses ferroptosis by inhibiting NEDD4L/ZRANB1 mediated ubiquitination and subsequent proteasomal degradation of the cystine-glutamate antiporter SLC7A11. Furthermore, metabolomic profiling of cancer cells revealed that LAPTM4B knockout leads to a significant enrichment of ferroptosis and associated metabolic alterations. By integrating results from cellular assays, patient tissue samples, an animal model, and cancer databases, this study highlights the clinical relevance of the LAPTM4B-SLC7A11-ferroptosis signaling axis in NSCLC progression and identifies it as a potential target for the development of cancer therapeutics.

M6A modification of lncRNA PHKA1-AS1 enhances Actinin Alpha 4 stability and promotes non-small cell lung cancer metastasis.

Cancer is a disease with molecular heterogeneity that is closely related to gene mutations and epigenetic changes. The principal histological subtype of lung cancer is non-small cell lung cancer (NSCLC). Long noncoding RNA (lncRNA) is a kind of RNA that is without protein coding function, playing a critical role in the progression of cancer. In this research, the regulatory mechanisms of lncRNA phosphorylase kinase regulatory subunit alpha 1 antisense RNA 1 (PHKA1-AS1) in the progression of NSCLC were explored. The increased level of N6-methyladenosine (m6A) modification in NSCLC caused the high expression of PHKA1-AS1. Subsequently, high-expressed PHKA1-AS1 significantly facilitated the proliferation and metastasis of NSCLC cells, and these effects could be reversed upon the inhibition of PHKA1-AS1 expression, both in vivo and in vitro. Additionally, the target protein of PHKA1-AS1 was actinin alpha 4 (ACTN4), which is known as an oncogene. Herein, PHKA1-AS1 could enhance the protein stability of ACTN4 by inhibiting its ubiquitination degradation process, thus exerting the function of ACTN4 in promoting the progress of NSCLC. In conclusion, this research provided a theoretical basis for further exploring the potential mechanism of NSCLC metastasis and searching novel biomarkers related to the pathogenesis and progression of NSCLC.

Remodelin delays non-small cell lung cancer progression by inhibiting NAT10 via the EMT pathway.

Lung cancer remains the foremost reason of cancer-related mortality, with invasion and metastasis profoundly influencing patient prognosis. N-acetyltransferase 10 (NAT10) catalyzes the exclusive N (4)-acetylcytidine (ac4C) modification in eukaryotic RNA. NAT10 dysregulation is linked to various diseases, yet its role in non-small cell lung cancer (NSCLC) invasion and metastasis remains unclear. Our study delves into the clinical significance and functional aspects of NAT10 in NSCLC. We investigated NAT10's clinical relevance using The Cancer Genome Atlas (TCGA) and a group of 98 NSCLC patients. Employing WB, qRT-PCR, and IHC analyses, we assessed NAT10 expression in NSCLC tissues, bronchial epithelial cells (BECs), NSCLC cell lines, and mouse xenografts. Further, knockdown and overexpression techniques (siRNA, shRNA, and plasmid) were employed to evaluate NAT10's effects. A series of assays were carried out, including CCK-8, colony formation, wound healing, and transwell assays, to elucidate NAT10's role in proliferation, invasion, and metastasis. Additionally, we utilized lung cancer patient-derived 3D organoids, mouse xenograft models, and Remodelin (NAT10 inhibitor) to corroborate these findings. Our investigations revealed high NAT10 expression in NSCLC tissues, cell lines and mouse xenograft models. High NAT10 level correlated with advanced T stage, lymph node metastasis and poor overall survive. NAT10 knockdown curtailed proliferation, invasion, and migration, whereas NAT10 overexpression yielded contrary effects. Furthermore, diminished NAT10 levels correlated with increased E-cadherin level whereas decreased N-cadherin and vimentin expressions, while heightened NAT10 expression displayed contrasting results. Notably, Remodelin efficiently attenuated NSCLC proliferation, invasion, and migration by inhibiting NAT10 through the epithelial-mesenchymal transition (EMT) pathway. Our data underscore NAT10 as a potential therapeutic target for NSCLC, presenting avenues for targeted intervention against lung cancer through NAT10 inhibition.

CircSLC25A16 facilitates the development of non-small-cell lung cancer through the miR-335-5p/CISD2 axis.

Non-small-cell lung cancer (NSCLC) is a common malignancy with high morbidity and mortality. Circular RNAs are widely involved in NSCLC progression. However, the mechanism of circSLC25A16 in NSCLC has not been reported. The expressions of circSLC25A16, microRNA-335-5p (miR-335-5p), and CDGSH iron-sulfur domain-containing protein 2 (CISD2) were monitored by quantitative real-time fluorescence polymerase chain reaction. Western blot was also carried out to measure the protein levels of CISD2, hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA). For functional analysis, cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine, flow cytometry, transwell, and wound healing assays were utilized to examine cell proliferation, apoptosis, and migration. Glucose uptake and lactate production were detected using commercial kits. The relationship between miR-335-5p and circSLC25A16 or CISD2 was verified by dual-luciferase reporter and RNA immunoprecipitation assays. Furthermore, tumor xenograft was established to explore the function of circSLC25A16 in vivo. CircSLC25A16 and CISD2 were overexpressed in NSCLC, but miR-335-5p was downregulated. CircSLC25A16 acted as a miR-335-5p sponge, and silencing of circSLC25A16 arrested cell proliferation, migration, and glycolysis, and promoted apoptosis, but these impacts were resumed by miR-335-5p inhibition. CISD2 was a miR-335-5p target, and overexpression of CISD2 abolished the suppressive function of miR-335-5p mimic on the malignant behavior of NSCLC cells. CircSLC25A16 could adsorb miR-335-5p to mediate CISD2 expression. Additionally, silencing circSLC25A16 restrained the growth of NSCLC tumor xenograft in vivo. CircSLC25A16 facilitated NSCLC progression via the miR-335-5p/CISD2 axis, implying that circSLC25A16 may serve as a novel biomarker for NSCLC treatment.

Downregulation of hsa_circTLK1 represses non-small cell lung cancer progression by regulating miR-876-3p/SRSF7 axis

BackgroundThis study clarified the expression of cicrTLK1 in non-small cell lung cancer (NSCLC) and explored its role in cancer growth, metastasis and immune escape, providing a potential molecular target and theoretical basis for NSCLC treatment. MethodsThe expression levels of circTLK1, miR-876-3p and SRSF7 were determined by RT-qPCR assay. The localization of circTLK1 in NSCLC cells was determined by FISH assay. EdU and cell plate clone formation assay were applied to explore cell proliferation. Wound healing test and Transwell assay were applied to measure the migration and invasion ability. Cell apoptosis rate was detected by FCM assay. Western blotting assay was adopted to measure the protein expression of SRSF7. Dual-luciferase reporter gene assay was applied to assess the interaction between miR-876-3p and circTLK1, and between miR-876-3p and SRSF7. The ability of cirTLK1 to regulate tumor formation in vivo was examined by tumor transplantation experiments in nude mice. ResultsThe relative expression of circTLK1 was increased in NSCLC cell lines. Knockdown of circTLK1 prohibited the proliferation, migration, and invasion, and promoted apoptosis rate, but miR-876-3p inhibitor reversed the effects of circTLK1 knockdown. In addition, silencing of circTLK1 overtly restrained the growth of transplanted tumors in vivo, and inhibited immune escape. In addition, circTLK1 interacted with miR-876-3p, and SRSF7 was concluded to be the target gene of miR-876-3p. ConclusionIn this study, we researched the inhibitory effect of circTLK1knockdown on NSCLC progression and immune escape, and further elucidated the potential regulatory mechanism of circTLK1/miR876-3p/SRSF7 axis.

Silencing of circRPPH1 Inhibits the Progression of Non-Small-Cell Lung Cancer Through miR-326/ERBB4 Signal Axis.

Circular RNAs (circRNAs) play critical roles in the recurrence and progression of non-small-cell lung cancer (NSCLC). This study aimed to investigate the function and underlying mechanism of a novel circRNA (circRPPH1) in NSCLC. Localization of circRPPH1 was determined via FISH assay, while cell proliferation was assessed via CCK8 and colony formation assay. Cell migration and invasion were studied using transwell assay, while binding sites between miR-326 and circRPPH1 or ERBB4 were verified by luciferase reporter, RIP, and RNA pull-down assays. Moreover, xenograft assay was performed to verify the in vivo roles of circRPPH1. Results indicated that circRPPH1 was highly expressed in NSCLC tissues and cells, where circRPPH1 levels were predictive of poor prognosis. The malignant behavior of NSCLC cells was exacerbated by overexpressing circRPPH1, while opposite effects were observed when it was knocked down. Direct interaction between miR-326 and circRPPH1 or ERBB4 was confirmed in NSCLC cells, while rescue experiment results showed that circRPPH1 exerted an oncogenic role via miR-326-ERBB4 signal axis. Moreover, in vitro, growth of NSCLC cells was significantly attenuated following circRPPH1 depletion. The study concluded that circRPPH1 was involved in promoting NSCLC progression via the miR-326/ERBB4 axis, which provided a novel potential target for the diagnosis or treatment of NSCLC.

NAT10-mediated upregulation of GAS5 facilitates immune cell infiltration in non-small cell lung cancer via the MYBBP1A-p53/IRF1/type I interferon signaling axis

Interactions of tumor cells with immune cells in the tumor microenvironment play an important role during malignancy progression. We previously identified that GAS5 inhibited tumor development by suppressing proliferation of tumor cells in non-small cell lung cancer (NSCLC). Herein, we discovered a tumor-suppressing role for tumor cell-derived GAS5 in regulating tumor microenvironment. GAS5 positively coordinated with the infiltration of macrophages and T cells in NSCLC clinically, and overexpression of GAS5 promoted macrophages and T cells recruitment both in vitro and in vivo. Mechanistically, GAS5 stabilized p53 by directly binding to MYBBP1A and facilitating MYBBP1A-p53 interaction, and enhanced p53-mediated transcription of IRF1, which activated type I interferon signaling and increased the production of downstream CXCL10 and CCL5. We also found that activation of type I interferon signaling was associated with better immunotherapy efficacy in NSCLC. Furthermore, the stability of GAS5 was regulated by NAT10, the key enzyme responsible for N4-acetylcytidine (ac4C) modification, which bound to GAS5 and mediated its ac4C modification. Collectively, tumor cell-derived GAS5 could activate type I interferon signaling via the MYBBP1A-p53/IRF1 axis, promoting immune cell infiltration and potentially correlating with immunotherapy efficacy, which suppressed NSCLC progression. Our results suggested GAS5 as a promising predictive marker and potential therapeutic target for combination therapy in NSCLC.A schematic diagram demonstrating the regulatory effect of GAS5 on immune cell infiltration by activating type I interferon signaling via MYBBP1A-p53/IRF1 axis in non-small cell lung cancer. IFN, interferon.

A novel prognostic signature based on smoking-associated genes for predicting prognosis and immune microenvironment in NSCLC smokers

BackgroundAs a highly heterogeneous tumor, non-small cell lung cancer (NSCLC) is famous for its high incidence and mortality worldwide. Smoking can cause genetic changes, which leading to the occurrence and progress of NSCLC. Nevertheless, the function of smoking-related genes in NSCLC needs more research.MethodsWe downloaded transcriptome data and clinicopathological parameters from Gene Expression Omnibus (GEO) databases, and screened smoking-related genes. Lasso regression were applied to establish the 7-gene signature. The associations between the 7-gene signature and immune microenvironment analysis, survival analysis, drug sensitivity analysis and enriched molecular pathways were studied. Ultimately, cell function experiments were conducted to research the function of FCGBP in NSCLC.ResultsThrough 7-gene signature, NSCLC samples were classified into high-risk group (HRG) and low-risk group (LRG). Significant difference in overall survival (OS) between HRG and LRG was found. Nomograms and ROC curves indicated that the 7-gene signature has a stable ability in predicting prognosis. Through the analysis of immune microenvironment, we found that LRG patients had better tumor immune activation. FCGBP showed the highest mutation frequency among the seven prognostic smoking related genes (LRRC31, HPGD, FCGBP, SPINK5, CYP24A1, S100P and FGG), and was notable down-regulated in NSCLC smokers compared with non-smoking NSCLC patients. The cell experiments confirmed that FCGBP knockdown promoting proliferation, migration, and invasion in NSCLC cells.ConclusionThis smoking-related prognostic signature represents a promising tool for assessing prognosis and tumor microenvironment in smokers with NSCLC. The role of FCGBP in NSCLC was found by cell experiments, which can be served as diagnostic biomarker and immunotherapy target for NSCLC.

Down-regulated expression of TIPE3 inhibits malignant progression of non-small cell lung cancer via Wnt signaling

Non-small cell lung cancer (NSCLC) accounts for approximately 80 % of all lung cancers with a low five-year survival rate. Therefore, the mechanistic pathways and biomarkers of NSCLC must be explored to elucidate its pathogenesis. In this study, we examined TIPE3 expression in NSCLC cells and investigated the molecular mechanisms underlying NSCLC regulation in vivo and in vitro. We collected tissue samples from patients with NSCLC to examine TIPE3 expression and its association with patient metastasis and prognosis. Furthermore, we evaluated the expression level of TIPE3 in NSCLC cells. Cell lines with the highest expression were selected for molecular mechanism experiments, and animal models were established for in vivo verification. The results showed that TIPE3 was significantly increased in patients with NSCLC, and this increased expression was associated with tumor metastasis and patient prognosis. TIPE3 knockdown inhibited proliferation, migration, invasion, EMT, angiogenesis, and tumorsphere formation in NSCLC cells. Moreover, it reduced the metabolic levels of tumor cells. However, overexpression of TIPE3 has the opposite effect. The in vivo results showed that TIPE3 knockdown reduced tumor volume, weight, and metastasis. Furthermore, the results showed that TIPE3 may inhibit malignant progression of NSCLC via the regulation of Wnt/β-catenin expression. These findings suggest that TIPE3 is significantly elevated in patients with NSCLC and that downregulation of TIPE3 can suppress the malignant progression of NSCLC, which could serve as a potential diagnostic and treatment strategy for NSCLC.

Curcumin Inhibits the Progression of Non-small Cell Lung Cancer by Regulating DMRT3/SLC7A11 Axis.

Non-small cell lung cancer (NSCLC) is a fatal malignancy all over the world. Emerging studies have shownthat curcumin might repress NSCLC progression by regulating ferroptosis, but the underlying mechanism remains unclear. 16HBE, LK-2, and H1650 cell viability was detected using Cell Counting Kit-8 assay. LK-2 and H1650 cell proliferation, apoptosis, and angiopoiesis were measured using 5-ethynyl-2'-deoxyuridine, flow cytometry, and tube formation assay. Superoxide dismutase, Malondialdehyde, Glutathione, and lactate dehydrogenase levels in LK-2 and H1650 cells were examined using special assay kits. Fe+ level was assessed using an iron assay kit. Doublesex and Mab-3 related Transcription Factor 3 (DMRT3) and solutecarrierfamily7member11(SLC7A11) protein levels were detected using western in NSCLC tissues, adjacent matched normal tissues, 16HBE cells, LK-2 cells, H1650 cells, and xenograft tumor tissues. Glutathione peroxidase 4, Acyl-CoA Synthetase Long Chain Family Member 4, and transferrinreceptor1 protein levels in LK-2 and H1650 cells were examined by western blot assay. DMRT3 and SLC7A11 levels were determined using real-time quantitative polymerase chain reaction. After JASPAR prediction, binding between DMRT3 and SLC7A11 promoter was verified using Chromatin immunoprecipitation and dual-luciferase reporter assays in LK-2 and H1650 cells. Role of curcumin on NSCLC tumor growth was assessed using the xenograft tumor model in vivo. Curcumin blocked NSCLC cell proliferation and angiopoiesis, and induced apoptosis and ferroptosis. DMRT3 or SLC7A11 upregulation partly abolished the suppressive role of curcumin on NSCLC development. In mechanism, DMRT3 was a transcription factor of SLC7A11 and increased the transcription of SLC7A11 via binding to its promoter region. Curcumin inhibited NSCLC growth in vivo by modulating DMRT3. Curcumin might constrain NSCLC cell malignant phenotypes partly through the DMRT3/SLC7A11 axis, providing a promising therapeutic strategy for NSCLC.

The anti-non-small cell lung cancer effect of Diosbulbin B: Targeting YY1 induced cell cycle arrest and apoptosis

BackgroundToxic components frequently exhibit unique characteristics and activities, offering ample opportunities for the advancement of anti-cancer medications. As the main hepatotoxic component of Dioscorea bulbifera L. (DB), Diosbulbin B (DIOB) has been widely studied for its anti-tumor activity at nontoxic doses. However, the effectiveness and mechanism of DIOB against non-small cell lung cancer (NSCLC) remains unclear. PurposeTo evaluate the anti-NSCLC activity of DIOB and to elucidate the specific mechanism of action. MethodThe effect of DIOB on NSCLCL in vitro was evaluated through CCK8, colony formation, and flow cytometry. The in vivo efficacy and safety of DIOB in treating NSCLC were assessed using various techniques, including HE staining, tunel staining, immunohistochemistry, and biochemical index detection. To understand the underlying mechanism, cell transfection, western blotting, molecular docking, cellular thermal shift assay (CESTA), and surface plasmon resonance (SPR) were employed for investigation. ResultsDIOB effectively hindered the progression of NSCLC both in vitro and in vivo settings at a no-observed-adverse-effect concentration (NOAEC) and a safe dosage. Specifically, DIOB induced significant G0/G1 phase arrest and apoptosis in A549, PC-9, and H1299 cells, while also notably inhibiting the growth of subcutaneous tumors in nude mice. Mechanistically, DIOB could directly interact with oncogene Yin Yang 1 (YY1) and inhibit its expression. The reduction in YY1 resulted in the triggering of the tumor suppressor P53, which induced cell cycle arrest and apoptosis in NSCLC cells by inhibiting the expression of Cyclin A2, B2, CDK1, CDK2, CDK4, BCL-2, and inducing the expression of BAX. In NSCLC cells, the induction of G0/G1 phase arrest and apoptosis by DIOB was effectively reversed when YY1 was overexpressed or P53 was knocked down. Importantly, we observed that DIOB exerted the same effect by directly influencing the expression of YY1-regulated c-Myc and BIM, particularly in the absence of P53. ConclusionFor the inaugural investigation, this research unveiled the anti-NSCLC impact of DIOB, alongside its fundamental mechanism. DIOB has demonstrated potential as a treatment agent for NSCLC due to its impressive efficacy in countering NSCLC.

The promotion of non-small cell lung cancer progression by collagen and calcium binding EGF domain 1 is mediated through the regulation of ERK/JNK/P38 phosphorylation by reactive oxygen species.

Reactive oxygen species (ROS) are metabolic by-products of cells, and abnormal changes in their levels are often associated with tumor development. Our aim was to determine the role of collagen and calcium binding EGF domain 1 (CCBE1) in oxidative stress and tumorigenesis in non-small cell lung cancer cells (NSCLC). We investigated the tumorigenic potential of CCBE1 in NSCLC using in vitro and in vivo models of CCBE1 overexpression and knockdown. Immunohistochemical staining results showed that the expression of CCBE1 in cancer tissues was significantly higher than that in adjacent tissues. Cell counting Kit 8, clonal formation, wound healing, and transwell experiments showed that CCBE1 gene knockdown significantly inhibited the migration, invasion, and proliferation of NSCLC cell lines. In terms of mechanism, the silencing of CCBE1 can significantly promote the morphological abnormalities of mitochondria, significantly increase the intracellular ROS level, and promote cell apoptosis. This change of oxidative stress can affect cell proliferation, migration, and invasion by regulating the phosphorylation level of ERK/JNK/P38 MAPK. Specifically, the downregulation of CCBE1 inhibits the phosphorylation of ERK/P38 and promotes the phosphorylation of JNK in NSCLC, and this regulation can be reversed by the antioxidant NAC. In vivo experiments confirmed that downregulating CCBE1 gene could inhibit the growth of NSCLC in BALB/c nude mice. Taken together, our results confirm the tumorigenic role of CCBE1 in promoting tumor invasion and migration in NSCLC, and reveal the molecular mechanism by which CCBE1 regulates oxidative stress and the ERK/JNK/P38 MAPK pathway.

Epithelial-mesenchymal transition induced by tumor cell-intrinsic PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-high lung cancer.

We investigated the role of tumor cell-intrinsic PD-L1 signaling in the epithelial-mesenchymal transition (EMT) in non-small-cell lung cancer (NSCLC) and the role of EMT as a predictive biomarker for immune checkpoint inhibitor (ICI) therapy. PD-L1-overexpressing or PD-L1-knockdown NSCLC cells underwent RNA-seq and EMT phenotype assessment. Mouse lung cancer LLC cells were injected into nude mice. Two cohorts of patients with NSCLC undergoing ICI therapy were analyzed. RNA-seq showed that EMT pathways were enriched in PD-L1-high NSCLC cells. EMT was enhanced by PD-L1 in NSCLC cells, which was mediated by transforming growth factor-β (TGFβ). PD-L1 promoted the activation of p38-MAPK by binding to and inhibiting the protein phosphatase PPM1B, thereby increasing the TGFβ production. Tumor growth and metastasis increased in nude mice injected with PD-L1-overexpressing LLC cells. In the ICI cohort, EMT signature was higher in patients with progressive disease than in those with responses, and EMT was significantly associated with poor survival in PD-L1-high NSCLC. In PD-L1-high NSCLC, EMT was associated with increased M2-macrophage and regulatory T-cell infiltrations and decreased cytotoxic T-cell infiltration. Tumor cell-intrinsic PD-L1 function contributes to NSCLC progression by promoting EMT. EMT may predict an unfavorable outcome after ICI therapy in PD-L1-high NSCLC.

Highly homologous miR-135a and miR-135b converting non-small cell lung cancer from suppression to progression via enhancer switching.

microRNAs (miRNAs) are short non-coding RNAs that have been increasingly recognized for their significant roles in the progression of cancer. Distinct miRNAs exhibit diverse functions attributed to variations in their sequences. As a result of possessing highly homologous seed sequences, these miRNAs target overlapping or similar gene sets, thus performing analogous roles. However, different from this sight, our study discovered that miR-135a-5p and miR-135b-5p, despite differing by only one nucleotide, exhibit distinct functional roles. Using non-small cell lung cancer (NSCLC) as a paradigm, our findings unveiled the downregulation of miR-135a-5p and upregulation of miR-135b-5p within NSCLC through TCGA database. Consequently, we further investigated their functional differences in A549 cells. Overexpression of miR-135b-5p enhanced the proliferation and migration capabilities of A549 cells, whereas miR-135a-5p transfection exhibited the opposite effect. We demonstrated that the activation of specific enhancers serves as a crucial mechanism underlying the disparate functions exerted by miR-135a-5p and miR-135b-5p in the context of NSCLC, consequently instigating a shift from inhibition to activation in NSCLC progression. Finally, we validated through animal experiments that miR-135b-5p promoted tumor progression, while miR-135a-5p exerted inhibitory effects on NSCLC development. This study offers a novel perspective for researchers to elucidate functional disparities exhibited by highly homologous miRNAs (miR-135a-5p and miR-135b-5p) in the context of NSCLC, along with the transition from inhibitory to progressive states in NSCLC. This study provides a solid foundation for future investigations into the functional roles of highly homologous miRNAs in pathological situation.

Analysis of Selected Toll-like Receptors in the Pathogenesis and Advancement of Non-Small-Cell Lung Cancer.

(1) Background: Non-small-cell lung cancer (NSCLC) represents a significant global health challenge, contributing to numerous cancer deaths. Despite advances in diagnostics and therapy, identifying reliable biomarkers for prognosis and therapeutic stratification remains difficult. Toll-like receptors (TLRs), crucial for innate immunity, now show potential as contributors to cancer development and progression. This study aims to investigate the role of TLR expression as potential biomarkers in the development and progression of NSCLC. (2) Materials and Methods: The study was conducted on 89 patients diagnosed with NSCLC and 40 healthy volunteers, for whom the prevalence of TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 was assessed on selected subpopulations of T and B lymphocytes in the peripheral blood of recruited patients along with the assessment of their serum concentration. (3) Result: Our study showed several significant changes in NSCLC patients at the beginning of the study. This resulted in a 5-year follow-up of changes in selected TLRs in recruited patients. Due to the high mortality rate of NSCLC patients, only 16 patients survived the 5 years. (4) Conclusions: The results suggest that TLRs may constitute real biomarker molecules that may be used for future prognostic purposes in NSCLC. However, further validation through prospective clinical and functional studies is necessary to confirm their clinical utility. These conclusions may lead to better risk stratification and tailored interventions, benefiting NSCLC patients and bringing medicine closer to precision.

Exosome-transported circ_0061407 and circ_0008103 play a tumour-repressive role and show diagnostic value in non-small-cell lung cancer

BackgroundCircular RNAs (circRNAs), one of the major contents of exosomes, have been shown to participate in the occurrence and progression of cancers. The role and the diagnostic potential of exosome-transported circRNAs in non-small-cell lung cancer (NSCLC) remain largely unknown.MethodsThe NSCLC-associated exosomal circ_0061407 and circ_0008103 were screened by circRNA microarray. The role of circ_0061407 and circ_0008103 in NSCLC was examined in vitro and in vivo. The encapsulation of the two circRNAs into exosomes and the transport to recipient cells were observed by confocal microscopy. The effects of exosome-transported circ_0061407 and circ_0008103 on recipient cells were investigated using a co-culture device. Bioinformatics analyses were performed to predict the mechanisms by which circ_0061407 and circ_0008103 affected NSCLC. The quantitative polymerase chain reaction was used to quantify the exosome-containing circ_0061407 and circ_0008103 in the serum samples of healthy, pneumonia, benign lung tumours, and NSCLC. The diagnostic efficacy was evaluated using receiver operating characteristic curves.ResultsThe levels of circ_0061407 and circ_0008103 within exosomes were down-regulated in the serum of patients with NSCLC. The up-regulation of circ_0061407 and circ_0008103 inhibited the proliferation, migration/invasion, cloning formation of NSCLC cells in vitro and inhibited lung tumour growth in vivo. Circ_0061407 and circ_0008103 were observed to be packaged in exosomes and transported to recipient cells, where they inhibited the proliferation, migration/invasion, and cloning formation abilities of the recipient cells. Moreover, circ_0061407 and circ_0008103 might be involved in the progression of NSCLC by interacting with microRNAs and proteins. Additionally, lower serum exosomal circ_0061407 and circ_0008103 levels were associated with advanced pathological staging and distant metastasis.ConclusionsThis study identified two novel exosome-transported circRNAs (circ_0061407 and circ_0008103) associated with NSCLC. These findings may provide additional insights into the development of NSCLC and potential diagnostic biomarkers for NSCLC.

TERC promotes non-small cell lung cancer progression by facilitating the nuclear localization of TERT

TERC promotes non-small cell lung cancer progression by facilitating the nuclear localization of TERT

Cuproptosis-related gene LIPT1 as a prognostic indicator in non-small cell lung cancer: Functional involvement and regulation of ATOX1 expression.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths, necessitating a deeper understanding of novel cell death pathways like cuproptosis. This study explored the relevance of cuproptosis-related genes in NSCLC and their potential prognostic significance. We analyzed the expression of 16 cuproptosis-related genes in 1017 NSCLC tumors and 578 Genotype-Tissue Expression (GTEx) normal samples from The Cancer Genome Atlas (TCGA) to identify significant genes. A risk model and prognostic nomogram were employed to identify the pivotal prognostic gene. Further in vitro experiments were conducted to investigate the functions of the identified genes in NSCLC cell lines. LIPT1, a gene for lipoate-protein ligase 1 enzyme, emerged as the central prognostic gene with decreased expression in NSCLC. Importantly, elevated LIPT1 levels were associated with a favorable prognosis for NSCLC patients. Overexpression of LIPT1 inhibited cell growth and enhanced apoptosis in NSCLC. We confirmed that LIPT1 downregulates the copper chaperone gene antioxidant 1 (ATOX1), thereby impeding NSCLC progression. Our study identified LIPT1 as a valuable prognostic biomarker in NSCLC as it elucidates its tumor-inhibitory role through the modulation of ATOX1. These findings offered insights into the potential therapeutic targeting of LIPT1 in NSCLC, contributing to a deeper understanding of this deadly disease.

Circ_0007432 promotes non-small cell lung cancer progression and macrophage M2 polarization through SRSF1/KLF12 axis

Circular RNAs (circRNAs) plays critical roles in non-small cell lung cancer (NSCLC) development. Herein, we illustrated the effects of circ_0007432 on malignant features of NSCLC. We found that circ_0007432 played a promoting role in NSCLC progression, lying in accelerating cell viability, migration and invasion of NSCLC cells, promoting M2 macrophage polarization, suppressing cell apoptosis of NSCLC cells, and enhancing tumor growth invivo. Mechanistically, the interactions among circ_0007432, SRSF1, KLF12, and IL-8 were validated by RNA-binding protein immunoprecipitation (RIP), electrophoretic mobility shift assay (EMSA), RNA pull-down, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP) assays. Circ_0007432 upregulated KLF12 by recruiting SRSF1. KLF12 facilitated IL-8 expression and release by binding to IL-8 promoter. Furthermore, the role of circ_0007432/SRSF1/KLF12/IL-8 axis in malignant phenotypes of tumor cells or macrophage polarization was investigated using rescue experiments. In conclusion, circ_0007432 bound with SRSF1 to stabilize KLF12 and then promote IL-8 release, thus promoting malignant behaviors of NSCLC cells and M2 macrophage polarization.

Mogrol-mediated enhancement of radiotherapy sensitivity in non-small cell lung cancer: a mechanistic study.

This study investigated mogrol's impact on non-small cell lung cancer (NSCLC) radiosensitivity and underlying mechanisms, using various methods including assays, bioinformatics, and xenograft models. CCK-8, clonogenic, flow cytometry, TUNEL, and Western blot assays evaluated mogrol and radiation effects on NSCLC viability and apoptosis. Ubiquitin-specific protease 22 (USP22) expression in NSCLC patient tissues was determined by RT-qPCR and Western blot. A xenograft model validated mogrol's effects on tumor growth. Bioinformatics identified four ubiquitin-specific proteases, including USP22, in NSCLC. Kaplan-Meier analysis confirmed USP22's value in lung cancer survival. Human Protein Atlas (HPA) database analysis indicated higher USP22 expression in lung cancer tissues. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis implicated ERK1/2 in NSCLC progression, and molecular docking showed stability between mogrol and ERK1/2. Further in vivo and in vitro experiments have demonstrated that mogrol enhances the inhibitory effect of radiation on NSCLC cell viability and clonogenic capacity. Cell viability and clonogenic capacity are reduced by >50%, and an increase in cellular apoptosis is observed, with apoptotic levels reaching 10%. USP22 expression was significantly elevated in NSCLC tissues, particularly in radiotherapy-resistant patients. Mogrol downregulated USP22 expression by inhibiting the ERK/CREB pathway, lowering COX2 expression. Mogrol also enhanced radiation's inhibition of tumor growth in mice. Mogrol enhances NSCLC radiosensitivity by downregulating USP22 via the ERK/CREB pathway, leading to reduced COX2 expression.NEW & NOTEWORTHY Mogrol enhances non-small cell lung cancer (NSCLC) cell sensitivity to radiotherapy by downregulating USP22 through the ERK/CREB pathway, reducing COX2 expression. These findings highlight mogrol's potential as an adjunct to improve NSCLC radiotherapy and open avenues for further research and clinical applications.