Pathogenesis Of Lung Cancer Research Articles

Exploring the Association Between PRC2 Genes Variants and Lung Cancer Risk in Chinese Han Population.

Genetic susceptibilities play a large role in the pathogenesis of lung cancer (LC). The polycomb repressive complex 2 (PRC2) is a conserved chromatin-associated complex that represses gene expression and is crucial for proper organismal development and gene expression patterns. Despite PRC2 dysregulation has been observed in various human cancers, the relationship between PRC2 genes variants and lung cancer risk remains largely unexplored. To investigate the association between single nucleotide polymorphisms (SNPs) in PRC2 genes and the risk of developing LC, we genotyped blood genomic DNA from 270 LC patients and 452 healthy individuals of Chinese Han ethnicity using the TaqMan™ genotyping technique. We found that rs17171119T>G(adjusted odds ratio (OR) = 0.662, 95% CI: 0.467-0.938, P < 0.05), rs10898459 T>C(adjusted OR = 0.615, 95% CI: 0.4-0.947, P < 0.05), and rs1136258 C>T(adjusted OR = 0.273, 95% CI: 0.186-0.401, P < 0.001) were significantly associated with a reduced risk of LC. Stratified analysis revealed a protective effect of rs17171119 in both male and female patients, specifically those with lung adenocarcinoma (LUAD). Additionally, rs1391221 showed a protective effect in both the LUAD and lung squamous cell carcinoma (LUSC) groups, while rs1136258 exhibited a protective effect in both females and males, as well as in both LUAD and LUSC groups. Furthermore, analysis of The Cancer Genome Atlas (TCGA) dataset revealed expression levels of EED and RBBP4 in both LUAD and LUSC. This study provides evidence that allelic variants in EZH2, EED, and RBBP4 may act as protective factors against LC development and could serve as genetic markers associated with susceptibility to LC.

Carrier-Free Inhalable Dry Microparticles of Celecoxib: Use of the Electrospraying Technique.

Upregulation of cyclooxygenase (COX-2) plays an important role in lung cancer pathogenesis. Celecoxib (CLX), a selective COX-2 inhibitor, may have beneficial effects in COVID-19-induced inflammatory storms. The current study aimed to develop carrier-free inhalable CLX microparticles by electrospraying as a dry powder formulation for inhalation (DPI). CLX microparticles were prepared through an electrospraying method using a suitable solvent mixture at two different drug concentrations. The obtained powders were characterized in terms of their morphology, solid state, dissolution behavior, and aerosolization performance. Electrosprayed particles obtained from the ethanol-acetone solvent mixture with a drug concentration of 3 % w/v exhibited the best in vitro aerosolization properties. The value of the fine particle fraction obtained for the engineered drug particles was 12-fold higher than that of the untreated CLX. When the concentration of CLX was increased, a remarkable reduction in FPF was obtained. The smallest median mass aerodynamic diameter was obtained from the electrosprayed CLX at a 3% concentration (2.82 µm) compared to 5% (3.25 µm) and untreated CLX (4.18 µm). DSC and FTIR experiments showed no change in drug crystallinity or structure of the prepared powders during the electrospraying process. The findings of this study suggest that electrospraying has potential applications in the preparation of DPI formulations.

Deep immune B and plasma cell repertoire in non-small cell lung cancer.

B cells, which have long been thought to be minor players in the development of anti-tumor responses, have been implicated as key players in lung cancer pathogenesis and response to checkpoint blockade in patients with lung cancer. Enrichment of late-stage plasma and memory cells in the tumor microenvironment has been shown in lung cancer, with the plasma cell repertoire existing on a functional spectrum with suppressive phenotypes correlating with outcome. B cell dynamics may be influenced by the inflammatory microenvironment observed in smokers and between LUAD and LUSC. Here, we show through high-dimensional deep phenotyping using mass cytometry (CyTOF), next generation RNA sequencing and multispectral immunofluorescence imaging (VECTRA Polaris) that key differences exist in the B cell repertoire between tumor and circulation in paired specimens from lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). In addition to the current literature, this study provides insight into the in-depth description of the B cell contexture in Non-Small Cell Lung Cancer (NSCLC) with reference to broad clinico-pathological parameters based on our analysis of 56 patients. Our findings reinforce the phenomenon of B-cell trafficking from distant circulatory compartments into the tumour microenvironment (TME). The circulatory repertoire shows a predilection toward plasma and memory phenotypes in LUAD however no major differences exist between LUAD and LUSC at the level of the TME. B cell repertoire, amongst other factors, may be influenced by the inflammatory burden in the TME and circulation, that is, smokers and non-smokers. We have further clearly demonstrated that the plasma cell repertoire exists on a functional spectrum in lung cancer, and that the suppressive regulatory arm of this axis may play a significant role in determining postoperative outcomes as well as following checkpoint blockade. This will require further long-term functional correlation. B and Plasma cell repertoire is very diverse and heterogeneous across different tissue compartments in lung cancer. Smoking status associates with key differences in the immune milieu and the consequent inflammatory microenvironment is likely responsible for the functional and phenotypic spectrum we have seen in the plasma cell and B cell repertoire in this condition.

The role of oncogenes and tumor suppressor genes in determining survival rates of lung cancer patients in the population of North Sumatra, Indonesia.

Background: Gaining a better understanding of molecular alterations in the pathogenesis of lung cancer reveals a significant change in approach to the management and prognosis of lung cancer. Several oncogenes and tumor suppressor genes have been identified and have different roles related to survival rates in lung cancer patients. This study aims to determine the role of KRAS, EGFR, and TP53 mutations in the survival rate of lung cancer patients in the population of North Sumatra. Methods: This is a retrospective cohort study involving 108 subjects diagnosed with lung cancer from histopathology specimens. DNA extractions were performed using FFPE followed by PCR examinations for assessing the expressions of EGFR, RAS, and TP53 protein. Sequencing analysis was carried out to determine the mutations of EGFR exon 19 and 21, RAS protein exon 2, and TP53 exon 5-6 and 8-9. Data input and analysis were conducted using statistical analysis software for Windows. The survival rate analysis was presented with Kaplan Meier. Results: 52 subjects completed all procedures in this study. Most of the subjects are male (75%), above 60 years old (53.8%), heavy smokers (75%), and suffer from adenocarcinoma type of lung cancer (69.2%). No subjects showed KRAS exon 2 mutations. Overall survival rates increased in patients with EGFR mutations (15 months compared to 8 months; p=0.001) and decreased in patients with TP53 mutations (7 months compared to 9 months; p=0.148). Also, there was increasing Progression-Free Survival in patients with EGFR mutations (6 months compared to 3 months) ( p=0.19) and decreasing PFS in patients with TP53 mutations (3 months compared to 6 months) ( p=0.07). Conclusions: There were no KRAS mutations in this study. EGFR mutations showed a higher survival rate, while TP53 mutations showed a lower survival rate in overall survival and progression-free survival.

Bi-directional interaction and predictive potential of inflammatory and oxidative stress-related biomarkers in patients with non-small cell lung cancer.

e15030 Background: Interplay between oxidative stress and inflammation play major role in the development and progression of various malignancies. As one of the most common and the deadliest malignancy, lung cancer has a prominent vicious cycle of oxidative stress and immune response. The aim of this study is to examine the inter-relationship between basic oxidative stress and inflammation-related plasma biomarkers in patients with non-small cell lung cancer (NSCLC) undergoing surgical resection procedure. Methods: After obtaining informed consent, pre-operative plasma levels of alpha-fetoprotein, nitrotyrosine, urokinase-type plasminogen activator, and myeloperoxidase (MPO) as oxidative stress-related biomarkers were determined in 49 patients with diagnosed NSCLC. In the same patient group, plasma levels of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), interferon gamma, tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and epidermal growth factor were also evaluated. Control samples were obtained from 34 healthy individuals. Plasma biomarkers were determined by enzyme-linked immunosorbent assay. Applicable statistical methods were used to analyze the data. Results: Positive correlation was observed between MPO and levels of the following inflammation-related biomarkers: IL-6 (r = 0.397, p = 0.007), VEGF (r = 0.494, p = 0.001), TNF-α (r = 0.348, p = 0.019), and MCP-1 (r = 0.377, p = 0.011). Biomarkers showing significance in correlation analysis were further analyzed by linear logistic regression in order to determine presence and strength of causality in each direction (oxidative stress to inflammation and inflammation to oxidative stress). IL-6 and VEGF were observed as a predictors of MPO levels (B = 0.334, p = 0.031, and B = 0.391, p = 0.039, respectively). Furthermore, causality was observed in the opposite direction as well. MPO levels were shown as a slightly better predictor of both IL-6 and VEGF plasma levels (B = 0.349, p = 0.007, and B = 0.433, p = 0.001, respectively), but also as a predictor of TNF-α and MCP-1 levels (B = 0.193, p = 0.019, and B = 0.217, p = 0.011, respectively). Conclusions: Conclusion: These studies showed a strong correlation between measured oxidative stress-related and inflammatory biomarkers. Furthermore, these observations underscore the importance of oxidative stress in the pathogenesis of lung cancer.

Prevalence of actionable oncogenic alterations (AGA) among patients with advanced (adv) non-squamous (NSQ) non-small cell lung cancer (NSCLC) by age, sex, and race in the United States (US).

e21206 Background: Identification of AGA in NSCLC has improved the understanding of lung cancer pathogenesis and introduced targeted therapies directed against specific genomic alterations. Given the limited data on the prevalence of AGA by demographics, we evaluated prevalence of AGA by age at diagnosis (dx), sex, and race. Methods: A descriptive study used the US nationwide de-identified Flatiron Health-Foundation Medicine NSCLC clinico-genomic database. Eligible patients were adults with a dx of adv NSQ NSCLC from Jan-2016 to Sep-2020 who initiated a first line therapy. The prevalence of AGA for each age, sex, or race stratum was calculated. Results: The cohort included 3938 patients; 67.9% White, 52.9% female, and median age at dx was 68 y. Table 1 presents the prevalence of AGA. The prevalence of EGFR and BRAF V600E mutations increased with age at dx. ALK rearrangement and ROS1 fusion were more prevalent among patients &lt; 50 y vs ≥50 y while MET exon 14 skipping mutation was more prevalent among patients ≥75 y vs &lt; 75 y. EGFR and KRAS G12C mutations were more prevalent in female vs male. Compared to White or Black, Asians had a higher prevalence of EGFR mutations and lower prevalence of KRAS G12C. Conclusions: The prevalence of certain AGA among patients with adv NSCLC vary by demographics, which may contribute to disproportionate disease burden in certain strata. These results highlight the need to enhance diversity of clinical trial populations and ensure the disease burden across demographics in the general population are represented in clinical trials. [Table: see text]

Establishment and Validation of Prognostic Model of Lung Adenocarcinoma Based on Apoptosis-Related Genes

Objective: Apoptosis is an autonomous cell death process controlled by genes that can keep the internal environment of cells relatively stable. Lately, many studies have shown that apoptosis plays an important role in the construction of tumor microenvironment, mainly through the release of a series of regulatory factors to control cell growth. Therefore, it is very valuable to find and explore the possible role of apoptosis in the pathogenesis of lung cancer and its impact on the prognosis of patients. Materials and Methods: We selected 10 apoptosis-related genes and used different statistical methods to construct a model to predict the survival and prognosis of patients with lung adenocarcinoma. Univariate and multivariate Cox analysis were used to evaluate the predictive power and value of prognostic models, as well as receiver operating characteristic (ROC) curve analysis. Results: We defined two subgroups (cluster1 and cluster2). Compared with cluster1, cluster2 was named "apoptosis inhibition subgroup". The survival prognosis of cluster1 was significantly better than that of cluster2, and the infiltration of immune cells in cluster2 suggested that its immune system was inhibited. Then, we established a new prognostic model of apoptosis-related genes to identify high-risk patients with lung adenocarcinoma. Two types of Cox proportional hazards analysis and ROC curve showed that our model can be used as a new independent factor for the prognosis of lung adenocarcinoma patients, and had strong predictive ability. Conclusion: Apoptosis is involved in the formation and development of lung adenocarcinoma and plays an important role. Our survival model can better predict the survival and prognosis of lung adenocarcinoma, and our study may be helpful for further research on new therapeutic targets and precise individualized treatment in the future.

Association between dietary approaches to stop hypertension eating pattern and lung cancer risk in 98,459 participants: results from a large prospective study.

Dietary approaches to stop hypertension (DASH) eating pattern is linked to anti-inflammatory responses and antioxidation, which overlap with the pathogenesis of lung cancer. However, there is insufficient epidemiological evidence to link this dietary pattern to lung cancer risk conclusively. To determine if adherence to the DASH diet is linked to a lower risk of developing lung cancer in a large prospective study. The data of participants were retrieved from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. A DASH score was calculated based on 8 dietary components to reflect adherence to DASH, with greater scores representing higher adherence. Three Cox proportional hazards models were constructed to analyze the association between DASH scores and lung cancer risk, including an unadjusted model and two adjusted models (model 1 for demographics and model 2 for fully confounding factors). A restricted cubic spline plot was utilized to illustrate the likelihood of developing lung cancer across the entire range of DASH scores. The association between each of the 8 DASH components and the risk of lung cancer was assessed separately. Several subgroup analyses were conducted to identify potential modifiers, and several sensitivity analyses were performed to verify the robustness of the findings. The study involved 98,459 individuals in total. The mean (standard deviation) DASH score was 24.00 (4.62) points, along with the mean follow-up period of 8.84 (1.94) years. Lung cancer was identified in 1642 cases over 869807.9 person-years of follow-up, and the overall incidence rate was 0.189 cases/100 person-years. Participants in the highest quartile in the fully adjusted model had a relatively decreased risk of developing lung cancer in comparison to those in the lowest quartile (HRquartile 4 versus 1: 0.647; 95% CI: 0.557, 0.752; Ptrend < 0.001). The restricted cubic spline plot demonstrated that DASH score and lung cancer risk were inversely associated and had a linear dose-response relationship (Pnon-linear = 0.944). According to subgroup analyses, those who were current or former smokers had a stronger inverse connection than those who never smoked (Pinteraction = 0.013). The results remained robust after several sensitivity analyses. The risk of lung cancer was inversely associated with DASH scores in the US population. This suggests that following the DASH pattern can help prevent lung cancer, especially for current or former smokers. More epidemiological evidence from other regions and populations is needed to confirm our findings.

Identification of the potential ferroptosis key genes in lung cancer with bone metastasis.

To identify the potential key genes of ferroptosis in the pathogenesis of lung cancer with bone metastasis (LCBM) by bioinformatics analysis to provide new targets for treating LCBM and an indicator for early monitoring. We first obtained differentially expressed genes (DEGs) associated with ferroptosis from the Gene Expression Omnibus (GEO) database. MiRWalk 2.0 was used to predict the key microRNAs (miRNAs) and construct related gene-miRNA interaction networks. The functional enrichment analysis of key miRNAs was performed using the miEAA database. Finally, the clinical data of 105 lung cancer patients were retrospectively analyzed, and logistic regression analysis was conducted to assess the relationship between serum alkaline phosphatase (ALP), neuron-specific enolase (NSE), and bone metastasis in lung cancer patients, and a receiver operating characteristic (ROC) curve was drawn. We identified 15 ferroptosis-related genes that were differentially expressed in lung cancer bone metastasis. GO and KEGG enrichment analyses suggested that these genes may affect the oxidative stress response, hypoxia response, rough endoplasmic reticulum, mitochondrial outer membrane, iron-sulfur cluster binding, virus receptor activity, central carbon metabolism in cancer, the interleukin-17 (IL-17) signaling pathway, and other aspects to participate in the occurrence and development of lung cancer bone metastasis. Among the 105 lung cancer patients included in the study, 39 cases had bone metastasis, and the incidence rate was 37.14%. A high Eastern Cooperative Oncology Group (ECOG) score and serum ALP and NSE overexpression were associated with bone metastasis in patients with lung cancer. By assessing the risk of bone metastasis in patients with lung cancer, we found that the Area Under Curves (AUCs) of serum ALP and NSE alone and combined were >0.70. The differentially expressed ferroptosis-related genes and predicted miRNA regulatory network in lung cancer bone metastasis and the related functional enrichment analysis provide new targets for the treatment of lung cancer bone metastasis. At the same time, from a serological perspective, it was found that early monitoring of serum ALP and NSE expression in patients with lung cancer could be considered to assess the risk of bone metastasis in the future.

USP5 knockdown alleviates lung cancer progression via activating PARP1-mediated mTOR signaling pathway

BackgroundWith the rapidly increasing morbidity and mortality, lung cancer has been considered one of the serious malignant tumors, affecting millions of patients globally. Currently, the pathogenesis of lung cancer remains unclear, hindering the development of effective treatment. This study aims to investigate the mechanisms of lung cancer and develop an effective therapeutic approach for intervention in preventing lung cancer progress.MethodsThe USP5 levels are detected in lung cancerous and paracancerous tissue by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting methods to explore their roles in lung cancer progression. MTT, colony assay, and transwell chamber approaches are employed to measure cell viability, proliferation, and migration, respectively. Further, flow cytometry experiments are performed to examine the effect of USP5 on lung cancer. Finally, the investigations in vivo are executed using the mice subcutaneous tumor model to identify the effect of USP5 in promoting lung cancer development.ResultsNotably, USP5 is highly expressed in lung cancer, USP5 overexpression promoted the proliferation and migration in the lung cancer cell lines, H1299 and A549, while knockdown of USP5 inhibited these via regulating the PARP1-mediated mTOR signaling pathway. Furthermore, the subcutaneous tumors model was established in C57BL/6 mice, and the volume of subcutaneous tumors was significantly reduced after silencing USP5, while increased after USP5 overexpression and decreased significantly with shRARP1 treatment at the same time.ConclusionsTogether, USP5 could promote the progression of lung cancer cells by mTOR signaling pathway and interacting with PARP1, indicating that USP5 may become a new target for lung cancer treatment.

NAA10 Hypomethylation is associated with particulate matter exposure and worse prognosis for patients with non-small cell lung cancer

ABSTRACT Airborne particulate matter (PM) is a major health hazard worldwide and is a key factor in lung cancer, which remains the most common type of malignancy and the leading cause of cancer-related deaths. DNA methylation is a critical mechanism underlying the detrimental effects of PM, however, the molecular link between PM exposure and lung cancer remains to be elucidated. N-α-acetyltransferase 10 (NAA10) is involved in the cell cycle, migration, apoptosis, differentiation, and proliferation. In order to investigate the role of NAA10 in PM-induced pathogenesis processes leading to lung cancer, we determined the expression and methylation of NAA10 in normal human bronchial epithelial (NHBE) cells treated with PM10, PM10-polycyclic aromatic hydrocarbons (PAH), and PM2.5 and evaluated the prognostic value of the NAA10 methylation status in lung cancer patients. Exposure to all PM types significantly increased the expression of NAA10 mRNA and decreased the methylation of the NAA10 promoter in NHBE cells compared with the mock-treated control. NAA10 hypomethylation was observed in 9.3% (13/140) of lung cancer tissue samples and correlated with NAA10 transcriptional upregulation. Univariate and multivariate analyses revealed that NAA10 hypomethylation was associated with decreased survival of patients with lung cancer. Therefore, these results suggest that PM-induced hypomethylation of the NAA10 may play an important role in the pathogenesis of lung cancer and may be used as a potential prognostic biomarker for lung cancer progression. Further studies with large numbers of patients are warranted to confirm our findings.

Abstract 6056: A nested case-control study of untargeted plasma metabolomics and lung cancer risk among never-smoking women in the prospective Shanghai Women’s Health Study

Abstract Background: The etiology of lung cancer among never-smokers is unclear despite 15% of cases in men and 53% in women worldwide are not smoking-related. Metabolomics provides a snapshot of dynamic biochemical activities, including those found to be driving tumor formation and progression. This study used untargeted metabolomics with network analysis to agnostically identify network modules and independent metabolites in pre-diagnostic blood samples among never-smokers to further understand the pathogenesis of lung cancer. Methods: Within the prospective Shanghai Women’s Health Study, we conducted a nested case-control study of 395 never-smoking incident lung cancer cases and 395 never-smoking controls matched on age. We performed liquid chromatography high-resolution mass spectrometry to quantify 20,348 unique metabolic features in plasma. Because metabolic features are expected to be highly correlated and more likely to be involved in biological processes as a network of intertwined features than individually, we agnostically constructed 28 network modules using a weighted correlation network analysis approach. The associations between metabolite network modules and individual metabolites with lung cancer were assessed using conditional logistic regression models, adjusting for age, body mass index, and exposure to environmental tobacco smoke. We accounted for multiple testing using a false discovery rate (FDR) &amp;lt; 0.20. Results: We identified a network module of 122 metabolic features enriched in lysophosphatidylethanolamines that was associated with all lung cancer combined (p = 0.001, FDR = 0.028) and lung adenocarcinoma (p = 0.002, FDR = 0.056) and another network module of 440 metabolic features that was associated with lung adenocarcinoma (p = 0.014, FDR = 0.196). Metabolic features were enriched in pathways associated with cell growth and proliferation, including oxidative stress, bile acid biosynthesis, and metabolism of nucleic acids, carbohydrates, and amino acids, including 1-carbon compounds. Conclusions: Our prospective study suggests that untargeted plasma metabolomics in pre-diagnostic samples could provide new insights into the etiology of lung cancer in never-smokers. Replication and further characterization of these associations are warranted. Citation Format: Mohammad L. Rahman, Xiao-Ou Shu, Douglas Walker, Dean P. Jones, Wei Hu, Bu-tian Ji, Batel Blechter, Jason YY Wong, Qiuyin Cai, Gong Yang, Tu-Tang Gao, Wei Zheng, Nathaniel Rothman, Qing Lan. A nested case-control study of untargeted plasma metabolomics and lung cancer risk among never-smoking women in the prospective Shanghai Women’s Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6056.

Abstract 3009: Measured and genetically-predicted leukocyte telomere length and lung cancer risk in the prospective UK Biobank

Abstract Telomere length is a biomarker reflective of aging and genomic instability. We previously found associations between longer measured leukocyte telomere length (LTL) and increased lung cancer risk in a pooled nested case-control study with 847 cases. Additionally, we reported that longer genetically-predicted telomere length (gTL) using a polygenic risk score (PRS) with 7 single nucleotide polymorphisms (SNPs) was associated with increased lung cancer risk among never-smoking Asian women. To investigate further, we conducted prospective cohort analyses of pre-diagnostic LTL and gTL in relation to risk of overall lung cancer and its subtypes in the UK Biobank. With over triple the number of cases, we had expanded statistical power to investigate lung cancer, adenocarcinoma (LUAD), and squamous cell carcinoma (SCC) among subgroups defined by smoking status and sex in this predominantly European study population. We analyzed 371,890 participants at baseline. Over the 12.36±1.64SD year follow-up, 2829 incident lung cancer cases were diagnosed, including 1078 LUAD and 487 SCC. LTL was measured using qPCR. Using European data, we calculated a weighted PRS for gTL. The PRS was derived from 130 linkage disequilibrium pruned SNPs (r2 &amp;gt; 0.01) associated with longer LTL in the UK Biobank. Multivariable Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of lung cancer in relation to log-transformed continuous and quartiles (Q) of LTL and gTL separately. Associations were estimated in the overall analytic sample and among smoking-sex subgroups. We conducted Mendelian Randomization (MR) analyses using MR-PRESSO with 130 genetic instruments to assess causal associations between LTL and lung cancer among Europeans.We found a strong dose-response relationship between longer LTL and increased lung cancer risk (p-trend= 2.6E-05), with the highest quartile being statistically significant (HRQ4vs.Q1=1.27, 95%CI: 1.15-1.42). The association was apparent for LUAD (p-trend=6.6E-10; HRQ4vs.Q1=1.78, 95%CI: 1.50-2.12), but not SCC. The lung cancer associations were prominent among never-smoking women (p-trend=4.0E-05) and never-smoking men (p-trend=2.0E-03). We also found dose-response relationships between longer gTL and risk of lung cancer (p-trend=4.2E-06) and LUAD (p-trend=2.1E-08). Additionally, we found evidence for causal associations between longer LTL and risk of lung cancer (HRper 1 SD gTL=1.87, 95%CI: 1.49-2.36, p=4.0E-07) and LUAD (HRper 1 SD gTL=2.45, 95%CI: 1.69-3.57, p=6.5E-06). Longer leukocyte telomere length potentially reflects biological processes relevant to the pathogenesis of lung cancer, particularly LUAD. Citation Format: Jason Yat-Yang Wong, Batel Blechter, Aubrey K. Hubbard, Jianxin Shi, Wei Hu, Mohammad Rahman, Shahinaz Gadalla, Mitchell Machiela, Nathaniel Rothman, Qing Lan. Measured and genetically-predicted leukocyte telomere length and lung cancer risk in the prospective UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3009.

Insights into Androgen Receptor Action in Lung Cancer

Sex hormones and their receptors play a crucial role in human sexual dimorphism and have been traditionally associated with hormone-dependent cancers like breast, prostate, and endometrial cancer. However, recent research has broadened our understanding by revealing connections with other types of cancers, such as lung cancer, where the androgen receptor has been found to be particularly significant. This review aims to explore the molecular mechanisms of androgen action in lung cancer pathogenesis and progression, highlighting the potential of inhibiting the androgen receptor signaling pathway as a therapeutic strategy for lung cancer treatment.

PYCR1 promotes the malignant progression of lung cancer through the JAK-STAT3 signaling pathway via PRODH-dependent glutamine synthesize

BackgroundLung cancer is a serious threat to human life. It is of great significance to elucidate the pathogenesis of lung cancer and search for new markers. This study evaluate the clinical value of pyrroline-5-carboxylate reductase 1 (PYCR1) and explore its role and mechanisms in the malignant progression of lung cancer. MethodsPYCR1 expression and its relationship with prognosis were analyzed using a bioinformatics database. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were utilized to examine the expression of PYCR1 in lung cancer tissues and peripheral blood. PYCR1-overexpressing lung cancer cells were constructed, then the cell proliferative, migration, and invasion ability was examined by the MTT and Transwell assays. siRNA against PRODH and STAT3 inhibitor sttatic was used to further elucidate the underlying mechanisms. Luciferase and CHIP assays were carried out for validate the how PYCR1 regulated PD-L1 expression via STAT3. Xenograft experiment was performed to determine the role of PYCR1 in vivo. ResultsDatabase analysis showed that PYCR1 expression was significantly increased in lung cancer tissues, and its high expression predicted poor prognosis. Lung cancer tissue and peripheral blood of patients showed obviously increased PYCR1 expression, and the sensitivity and specificity of serum PYCR1 in the diagnosis of lung cancer were 75.7% and 60%, respectively. PYCR1 overexpression enhanced the proliferative, migration, and invasion abilities of lung cancer cells. Both PRODH silence and stattic effectively attenuated the function of PYCR1. Animal experiment and IHC data indicated that PYCR1 could activated STAT3 phosphorylation and PD-L1, as well as suppressed T cell infiltration in lung cancer. Finally, we also validated that PYCR1 promoted PD-L1 transcription by elevating STAT3 binding to the gene promoter. ConclusionPYCR1 has certain value in the diagnosis and prognosis of lung cancer. Moreover, through regulating JAK-STAT3 signaling pathway, PYCR1 significantly participated in process of lung cancer progression via the metabolism link between proline and glutamine, indicating that PYCR1 might be also a novel therapeutic target.

Lung microbiome: an emerging player in lung cancer pathogenesis and progression.

The microbiome of the lungs, although until recently neglected, is now emerging as a potential contributor to chronic lung diseases, including cancer. Preclinical evidence suggests that the microbial burden of the lungs shapes the host immunity mechanisms and affects local antitumor immune responses. Studies of cohorts of patients with lung cancer reveal that different microbiome profiles are detected in patients with lung cancer compared to controls. In addition, an association between differential lung microbiome composition and distinct responses to immunotherapy has been suggested, yet, with limited data. Scarce evidence exists on the role of the lung microbiome in the development of metastases in the lungs. Interestingly, the lung microbiome is not isolated and interacts with the gut microbiome through a dynamic axis. Future research on the involvement of the lung microbiome in lung cancer pathogenesis and potential therapeutic implications is greatly anticipated.

The Role of Pembrolizumab (Keytruda) in Treating Non-small Cell Lung Cancer

Lung cancer also cause causes most of the cancer death cases around the world. In 2020, 1,796,144 people from all the world were estimated to die because of it. Lung cancer is responsible for one-fourth of all cancer death cases. There are many risk factors for lung cancer, including air pollution and cigarettes. Genes also play an important role in the pathogenesis of lung cancer. There are many types of treatment for it nowadays and they are used in different stages or different combinations. Treatment of NSCLC is influenced by the patient's overall health status, tumor stage, and pathological type. However, most of them have lots of side effects, such as bone marrow suppression, liver and kidney damage, etc. Compared to those treatments, immune checkpoint inhibitors less side effects. Pembrolizumab (Keytruda) is one of the inhibitors, which has a good performance in treating the NSCLC. Pembrolizumab inhibits the binding of PD-1 to PD-L1 and has shown good results in many clinical experiments. However, it also has limitations. As a result, this paper will introduce non-small cell lung cancer, Pembrolizumab (Keytruda), and its function in treating this disease.

IL-36 expression is increased in NSCLC with IL-36 stimulation of lung cancer cells promoting a pro-tumorigenic phenotype

The IL-36 cytokines are a recently described subset of the IL-1 family of cytokines, and have been shown to play a role in the pathogenesis of respiratory diseases such as asthma and COPD. Given the common aetiological links between COPD and lung cancer development, as well as the involvement of other IL-1 family members in lung tumorigenesis, the aim of this work was to investigate the role of IL-36 cytokines in the pathogenesis of lung cancer. In this study we demonstrate that expression of IL-36 cytokines and receptor mRNA and protein are significantly increased in lung cancer tissue compared to adjacent non-tumour tissue. In vitro assays showed that stimulation of two lung cancer cell lines, SKMES-1 human squamous cell and LLC murine lung cancer, with IL-36R agonists resulted in increased cellular migration and proliferation. All IL-36 cytokines induced the expression of pro-inflammatory chemokines in both lung cancer cell lines with synergistic effects identified upon co-stimulation of cells with IL-17, IL-22 and TNFα. Furthermore, we report that IL-36 cytokines induce protein expression of the immune checkpoint inhibitor protein PD-L1 on lung cancer cells. Taken together, this data indicates that targeting IL-36R signalling may be a useful targeted therapy for lung cancer patients with IL-36R+ cancer cells.

Identifying polymorphic cis-regulatory variants as risk markers for lung carcinogenesis and chemotherapy responses in tobacco smokers from eastern India

Aberrant expression of xenobiotic metabolism and DNA repair genes is critical to lung cancer pathogenesis. This study aims to identify the cis-regulatory variants of the genes modulating lung cancer risk among tobacco smokers and altering their chemotherapy responses. From a list of 2984 SNVs, prioritization and functional annotation revealed 22 cis-eQTLs of 14 genes within the gene expression-correlated DNase I hypersensitive sites using lung tissue-specific ENCODE, GTEx, Roadmap Epigenomics, and TCGA datasets. The 22 cis-regulatory variants predictably alter the binding of 44 transcription factors (TFs) expressed in lung tissue. Interestingly, 6 reported lung cancer-associated variants were found in linkage disequilibrium (LD) with 5 prioritized cis-eQTLs from our study. A case–control study with 3 promoter cis-eQTLs (p < 0.01) on 101 lung cancer patients and 401 healthy controls from eastern India with confirmed smoking history revealed an association of rs3764821 (ALDH3B1) (OR = 2.53, 95% CI = 1.57–4.07, p = 0.00014) and rs3748523 (RAD52) (OR = 1.69, 95% CI = 1.17–2.47, p = 0.006) with lung cancer risk. The effect of different chemotherapy regimens on the overall survival of lung cancer patients to the associated variants showed that the risk alleles of both variants significantly decreased (p < 0.05) patient survival.

Erken Evre Küçük Hücreli Dışı Akciğer Kanserli Hastalarda Tiyol-Disülfid Homeostazisin Prognoz Üzerine Etkisi

Objective: Lung cancer has a poor prognosis. Thiol groups with high antioxidant capacity are converted to disulfide bonds through biochemical reactions that neutralize different oxidant compounds. The thiol-disulfide (SH-SS) homeostasis has significant effects on cell mechanisms, transcription, and apoptosis. Here we present the prognostic role of dynamic SH-SS homeostasis in patients operated for NSCLC. Materials and Methods: Patients operating for early-stage NSCLC were prospectively analyzed. SH-SS homeostasis tests were measured using the automated spectrophotometric method. Results: This study enrolled 138 subjects, including 77 patients and 61 healthy controls. Native thiol and total thiol levels were significantly lower in the patient group. The disulfide-to-native thiol ratio, which is an indicator of oxidative stress in SH-SS homeostasis, also reached a level of statistical significance in the patient group (p&amp;lt;0.001). According to the cut-off values (305 and 326.3), the median overall survival rate was significantly shorter in patients with low native thiol and total thiol levels (p&amp;lt;0.001). Conclusions: This study demonstrated decreased native thiol and total thiol levels as well as decreased disulfide levels and SS/SH ratio in early-stage NSCLC. Impaired SH-SS homeostasis may contribute to lung cancer pathogenesis and poor prognosis because of enhanced oxidative stress.