Treatment Of Lung Adenocarcinoma Research Articles

Hsa_circ_0001492 regulates the hsa-miR-145-5p/ovarian carcinoma immunoreactive antigen domain 2 axis to promote the progression of lung adenocarcinoma.

Circular RNA (circRNA) has been proven to be a key regulator in a range of tumor illnesses, such as lung adenocarcinoma (LUAD); however, the regulatory mechanisms of circRNA remain unclear. In this study, circRNA (hsa_circ_0001492) in LUAD was examined for its regulatory and functional potential. qRT-PCR was used to assess the hsa_circ_0001492 level in LUAD. The RNAse R digestion test was employed to isolate hsa_circ_0001492. The primary location of hsa_circ_0001492 enrichment in LUAD cells was identified through a nucleoplasmic separation test. LUAD cell migration, proliferation, and spherogenicity were examined using wound healing, transwell, EdU, and cell spherogenicity assays. The association between miR-145-5p and hsa_circ_0001492/ovarian carcinoma immunoreactive antigen domain 2 (OCIAD2) was validated using a dual luciferase experiment. The interaction between sh-hsa_circ_0001492 and miR-145-5p was confirmed through an RNA pull-down assay. The effects of hsa_circ_0001492, miR-145-5p, and OCIAD2 on LUAD tumor development were examined using xenograft mouse models and immunohistochemistry tests. Results showed a higher amount of hsa_circ_0001492 in LUAD. The cytoplasm of LUAD cells was observed in the area where hsa_circ_0001492 mainly accumulated; hsa_circ_0001492 enhanced LUAD cell migration, proliferation, and sphere-forming ability. MiR-145-5p and OCIAD2 were identified as targets of hsa_circ_0001492 and miR-145-5p, respectively. The level of OCIAD2 was increased by hsa_circ_0001492 through targeted binding to miR-145-5p. In nude mice, tumor growth was inhibited by silencing hsa_circ_0001492, while knockdown of miR-145-5p and overexpression of OCIAD2 promoted the growth of LUAD tumors. In conclusion, hsa_circ_0001492 regulates the hsa-miR-145-5p/OCIAD2 axis to promote the progression of LUAD, and could be a useful target for the diagnosis and treatment of LUAD.

Treatment of lung adenocarcinoma with chemotherapy helps mitigate chronic myeloid leukaemia progression: A case report

Treatment of lung adenocarcinoma with chemotherapy helps mitigate chronic myeloid leukaemia progression: A case report

Immune regulation and prognostic prediction model establishment and validation of PSMB6 in lung adenocarcinoma

Lung cancer is one of the most common malignant tumors, and patients are often diagnosed at an advanced stage, posing a substantial risk to human health, so it is crucial to establish a model to forecast the prognosis of patients with lung cancer. Recent research has indicated that proteasome 20S subunit 6 (PSMB6) may be closely associated with anti-apoptotic pathways, and proliferation transduction signals in tumor cells of different tumors. However, the precise role of PSMB6 in the immunoregulatory processes within lung adenocarcinoma (LUAD) is yet to be elucidated. By analyzing the TCGA database, we discovered a positive correlation between the expression of PSMB6 and tumor growth trends, and lung adenocarcinoma patients with elevated PSMB6 expression levels had a worse prognosis. Our findings suggest a close correlation between PSMB6 expression levels, immune cell infiltration and immune checkpoint gene expression, which suggests that PSMB6 may become a new independent prognostic indicator. In addition, we developed a prognostic model of PSMB6-regulated immune infiltration-associated genes by analyzing the link between PSMB6 and the immune microenvironment. This model can not only predict the prognosis of lung adenocarcinoma but also forecasts the patient’s reaction to immunotherapy. The validity of this research outcome has been confirmed by the GSE31210 and IMvigor210 cohorts. Analysis of the Kaplan-Meier Plotter database indicates that individuals with elevated levels of PSMB6 expression exhibit a poorer prognosis. Additionally, in vitro experiments demonstrated that knockdown of PSMB6 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells while promoting their apoptosis. Overall, our findings suggest that PSMB6 could remarkably influence the management and treatment of lung adenocarcinoma, opening new avenues for targeted immunotherapeutic strategies.

Construction of a disulfidptosis-associated lncRNAs risk model to predict prognosis and immuno-infiltration analysis of lung adenocarcinoma

Objective: To develop a risk model based on LncRNAs associated with disulfidptosis to forecast the prognosis and assess immune infiltration of Lung adenocarcinoma (LUAD). Methods: This study employed a bioinformatics approach. The study was conducted from March 29, 2023 and concluded on July 1, 2023 at Guangzhou University of Chinese Medicine, Guangzhou, China. Transcriptomic data specific to LUAD were collected from TCGA database. Disulfidptosis-related LncRNAs were preliminarily screened using co-expression analysis, followed by screening using Lasso regression and Cox regression to identify LncRNAs. Subsequently, prognostic prediction models were constructed. To assess the model, survival analysis, subject operating characteristic curves, and calibration curves were employed. To evaluate the tumor microenvironment, the “estimate” package was used, while the “ggpubr” package was utilized to visualize the variations. Additionally, we employed CIBERSORT to examine immune cell infiltration abundance. Results: A prognostic prediction model was constructed using five LncRNAs. The high-risk group displayed a shorter overall survival and progression-free survival (P<0.05). The concordance index was calculated as 0.704 (95% CI: 0.654-0.754). GSEA analysis reveals that high risk group is associated with the cell cycle pathway and steroid hormone biosynthesis pathway, while the low-risk group is associated with hematopoietic cell pathway and allograft rejection pathway. Immune cell infiltration analysis indicated associations between the prognostic model and activated T cells CD4 memory, T cells CD8, etc. Conclusions: The risk model of Disulfidptosis-related LncRNAs can predict the prognosis of LUAD and evaluate the immune infiltration, providing a new direction for the treatment of LUAD. doi: https://doi.org/10.12669/pjms.40.10.9025 How to cite this: Liu J, Nie H, Du W, Song W. Construction of a disulfidptosis-associated lncRNAs risk model to predict prognosis and immuno-infiltration analysis of lung adenocarcinoma. Pak J Med Sci. 2024;40(10):2368-2372. doi: https://doi.org/10.12669/pjms.40.10.9025 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

MAZ promotes tumor proliferation and immune evasion in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most dominant histological subtype of lung cancer and one of the most lethal malignancies. The identification of novel therapeutic targets is required for the treatment of LUAD. Here, we showed that MYC-associated zinc-finger protein (MAZ) is upregulated in LUAD tissues. MAZ expression levels are inversely correlated with patient survival. Silencing of MAZ decreased tumor proliferation and the expression of pro-tumorigenic chemokines and Galectin-9 (Gal-9), an immune checkpoint molecule. The pro-tumorigenic chemokines and Gal-9 induce immune suppression by recruitment of myeloid cells and inhibition of T cell activation, respectively. Mechanistically, MAZ transcriptionally regulates KRAS expression and activates its downstream AKT-NF-κB signaling pathway, which is crucial for tumor progression and immune evasion. Additionally, in vivo animal models and bioinformatic analyses indicated that MAZ suppression could enhance the efficacy of immune checkpoint blockade (ICB) therapy for LUAD. Overall, our results suggest that MAZ plays an important role in regulating cell proliferation and immune evasion via KRAS/AKT/NF-κB signaling in LUAD. Our findings offer a candidate molecular target for LUAD therapy, with implications for improving the efficacy of ICB therapy.

TMEM164 promotes ferroptosis by selectively mediating ATG5-dependent autophagosome formation to inhibit the progression of LUAD

The study focuses on lung adenocarcinoma (LUAD), a predominant type of lung cancer. Despite advancements in diagnostics and molecular therapies, treatment remains challenging due to its low five-year survival rate. This study aims to investigate the role of the transmembrane protein TMEM164 in ferroptosis and anti-tumor immunity in LUAD, and to evaluate its potential as a therapeutic target. Through cellular experiments (such as QPCR, WB, CCK-8, EdU, Transwell, flow cytometry, CO-IP) and animal model experiments (including HE staining and IHC analysis), the relationship between TMEM164 expression and LUAD progression was explored, with particular attention to its mechanisms in ferroptosis and autophagy. The results show that TMEM164 expression is downregulated in LUAD and is associated with poor prognosis. Increasing TMEM164 expression significantly inhibits cell proliferation, migration, and invasion, while promoting an autophagy process dependent on ATG5 for autophagosome formation, thus facilitating ferroptosis. In mouse models, high TMEM164 expression combined with anti-PD-1 antibodies demonstrated synergistic anti-tumor effects. These findings highlight the critical role of TMEM164 in LUAD, suggesting that modulating TMEM164 expression could open new avenues for LUAD treatment.

6857 Adrenal Incidentaloma In A Patient With Surgically Treated Lung Adenocarcinoma A Decade After Complete Remission

Abstract Disclosure: L. Kaur: None. R. Kaur: None. F. Haider: None. A. Iqbal: None. N. Patel: None. Adrenal incidentaloma is an adrenal mass >1 cm in size commonly discovered incidentally in up to 5-7% of patients on imaging performed for reasons other than adrenal causes. Metastasis to the adrenal glands is common due to their rich blood supply, with lung cancer being the most common primary site, followed by the stomach, esophagus and the liver. Bilateral adrenal metastasis is common, however isolated metachronous or synchronous adrenal metastasis is rare, with an incidence of 1-6%. We present a case of incidentally discovered isolated right adrenal mass ten years after curative surgical resection of right lung adenocarcinoma. A 74 year old male with history significant for adenocarcinoma of the right upper lung lobe stage 1A , negative for metastasis status post lobectomy and no adjuvant chemotherapy or radiation 10 years ago presented to the hospital for his routine follow up evaluation. His vitals were within normal limits and physical examination was unremarkable. The follow up diagnostic CT imaging was done which showed an incidental 2.1 x 1.6 x 1.2 cm right adrenal mass without any pathological lesion or lymphadenopathy. A review of CT scan done one year ago revealed no prior adrenal mass or other suspicious findings. The patient was referred to endocrinology for evaluation of the adrenal mass. He denied abdominal or right flank pain, headaches, palpitations, elevated blood pressure, sweating, muscle weakness, weight gain/loss and was healthy appearing. Lab work up including biochemical studies for hormonal over production, including aldosterone-renin ratio, adrenocorticotropic hormone, plasma catecholamines with urine metanephrines and urine cortisol were within physiological ranges. CT scan was repeated after 2 months which revealed right adrenal mass of 3.2 x 1.8 x 1.7 cm in size with heterogeneity and high pre contrast density. Given the patient's history of lung cancer, imaging characteristics and rapid interval increase in size, there was high suspicion for metastatic disease. Other differentials considered due to fast growth rate included adrenocortical carcinoma and less likely adrenal adenoma. A decision was made to proceed with right adrenalectomy for definitive resection and histological diagnosis secondary to quickly growing adrenal mass with no lymphadenopathy. The patient underwent laparoscopic adrenalectomy and the final pathological report was consistent with metastatic lung adenocarcinoma. Postoperatively the patient recovered well. At 2 week and 3 month follow up he reported no concerns. Isolated adrenal metastasis is unusual and rare but may occur in lung cancer patients years after curative resection of the primary tumor and hence long term annual follow up imaging and monitoring is recommended for prompt diagnosis and timely treatment. Presentation: 6/2/2024

P1.08C.01 Targeted Therapy or Chemotherapy as Neoadjuvant Treatment for Resectable Stage II-IIIB EGFRm Lung Adenocarcinoma: A Study Between Four Cohorts

P1.08C.01 Targeted Therapy or Chemotherapy as Neoadjuvant Treatment for Resectable Stage II-IIIB EGFRm Lung Adenocarcinoma: A Study Between Four Cohorts

Identifying Luteolin as a Potential Drug for Treating Lung Adenocarcinoma with COVID-19 Affection based on Integration Analysis of Pharmacology and Transcriptome.

Lung adenocarcinoma (LUAD) is a major type of lung cancer worldwide, and under the pandemic coronavirus disease 2019 (COVID-19), its cancer burden is enlarged. This study aimed to explore potential drug targets and potential drugs for developing effective treatments for patients with both lung cancer and COVID-19. The interaction network of molecule compounds-target genes was constructed based on Traditional Chinese Medicines (TCMs) and gene expression data from public databases. The potential effectiveness of drugs was analyzed by molecular docking and molecular dynamics simulation. Western blot, transfection assay, Immunohistochemistry (IHC) staining, and flow cytometry were performed to investigate the function of HSP90AA1 in LUAD cells. Eight target genes (GSK3B, HMOX1, HSP90AA1, ICAM1, MAPK1, PLAU, RELA and TNFSF15.) were identified, and two of them (HSP90AA1 and RELA) were significantly associated with LUAD prognosis. Luteolin was discovered to bind with HSP90AA1. Moreover, in vitro cell experiments demonstrated that HSP90AA1 had higher expression in A549 cells, promoted cell viability and suppressed apoptosis in A549 cells and H1299 cells. HSP90AA1 was a target gene for further designing effective drugs for LUAD patients. Luteolin was a potential drug for treating patients with both LUAD and COVID-19.

MiR-140-3p Improves Sensitivity to Docetaxel by Suppressing PD-L1/ABCG2/MVP Expression in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC) accounts for the majority of non-small cell lung cancer (NSCLC), and overexpression of programmed death ligand 1 (PD-L1) in these cells is known to induce tumor immune evasion or drug resistance. However, detailed studies are needed to determine whether microRNAs (miRNAs) that reduce PD-L1 expression can suppress drug resistance in NSCLC. Kaplan Meier plotter and Receiver Operating Characteristic plotter were used to determine the effect of specific miRNAs on survival and chemotherapy response in NSCLC patients. Cell viability, colony formation and invasion assays, and qPCR analyses were also performed. The expression of miRNA-140-3p (miR-140-3p) was lower in LUAD patients, compared to the normal group, and low expression of miR-140-3p was associated with poor survival of LUAD patients, but not in LUSC. The miR-140-3p mimic inhibited proliferation, colony formation, and invasion of LUAD cells. Interestingly, the expression of miR-140-3p was significantly lower in the group of LUAD patients who did not respond to docetaxel. In LUAD cells, combined treatment with miR-140-3p and docetaxel significantly reduced cell viability as well as the expression of ABCG2 and MVP, genes associated with drug resistance, compared to either treatment alone. Additionally, combined injection of miR-140-3p mimic and docetaxel significantly inhibited tumor growth compared to treatment with docetaxel alone. These results suggest that the high expression of miR-140-3p in LUAD is correlated with good patient prognosis and may contribute to the treatment of LUAD, especially by increasing responsiveness to docetaxel.

Development and validation of machine learning models for diagnosis and prognosis of lung adenocarcinoma, and immune infiltration analysis.

The aim of our study was to develop robust diagnostic and prognostic models for lung adenocarcinoma (LUAD) using machine learning (ML) techniques, focusing on early immune infiltration. Feature selection was performed on The Cancer Genome Atlas (TCGA) data using least absolute shrinkage and selection Operator (LASSO), random forest (RF), and support vector machine (SVM) algorithms. Six ML algorithms were employed to construct the diagnostic models, which were evaluated through receiver operating characteristic (ROC) curves, precision-recall curves (PRC), and classification error (CE), and validated on the GSE7670 dataset. Additionally, a lasso cox prognostic model was built on the TCGA-LUAD dataset and externally validated using independent Gene Expression Omnibus datasets (GSE30219, GSE31210, GSE50081, and GSE37745). Single-sample gene set enrichment analysis (ssGSEA) was performed to assess immune cell infiltration in stage I LUAD samples, revealing significant differences in immune cell types. These findings demonstrate a positive correlation between immune infiltration in stage I LUAD and Th2 cells, Tcm cells, and T helper cells, while a negative correlation was observed with Macrophages, Eosinophils, and Tem cells. These insights provide novel perspectives for clinical diagnosis and treatment of LUAD.

SMARCA4 mutations and expression in lung adenocarcinoma: prognostic significance and impact on the immunotherapy response.

The switch/sucrose non-fermenting (SWI/SNF) complex family includes important chromatin-remodeling factors that are frequently mutated in lung adenocarcinoma (LUAD). However, the role of one family member, SMARCA4, in LUAD prognosis and immunotherapy sensitivity remains unclear. In the present study, 6745 LUAD samples from the cBioPortal database were used to analyze the relationships between SMARCA4 mutations and patient prognoses and clinical characteristics. Additionally, we examined the correlation between SMARCA4 mutations and prognosis in patients treated with immunotherapy using two immune-related datasets. SMARCA4 mutations and low expression were associated with shorter survival, and mutations were associated with a high tumor mutational burden and high microsatellite instability. SMARCA4 mutations were accompanied by KRAS, KEAP1, TP53 and STK11 mutations. No significant difference was observed in the immunotherapy response between patients with and without SMARCA4 mutations. When KRAS or STK11 mutations were present, immunotherapy effectiveness was poorer; however, when both SMARCA4 and TP53 mutations were present, immunotherapy was more effective. Furthermore, low SMARCA4 expression predicted a higher immunophenoscore, and SMARCA4 expression was correlated with certain immune microenvironment features. Taken together, our results suggest that SMARCA4 mutations and low expression might be associated with poor LUAD prognosis. Additionally, immunotherapy efficacy in patients with SMARCA4 mutations depended on the co-mutant genes. Thus, SMARCA4 could be an important factor to be considered for LUAD diagnosis and treatment.

The prognostic value of bioinformatics analysis of ECM receptor signaling pathways and LAMB1 identification as a promising prognostic biomarker of lung adenocarcinoma.

The extracellular matrix (ECM) is a complex and dynamic network of cross-linked proteins and a fundamental building block in multicellular organisms. Our study investigates the impact of genes related to the ECM receptor interaction pathway on immune-targeted therapy and lung adenocarcinoma (LUAD) prognosis. This study obtained LUAD chip data (GSE68465, GSE31210, and GSE116959) from NCBI GEO. Moreover, the gene data associated with the ECM receptor interaction pathway was downloaded from the Molecular Signature Database. Differentially expressed genes were identified using GEO2R, followed by analyzing their correlation with immune cell infiltration. Univariate Cox regression analysis screened out ECM-related genes significantly related to the survival prognosis of LUAD patients. Additionally, Lasso regression and multivariate Cox regression analysis helped construct a prognostic model. Patients were stratified by risk score and survival analyses. The prognostic models were evaluated using receiver operating characteristic curves, and risk scores and prognosis associations were analyzed using univariate and multivariate Cox regression analyses. A core gene was selected for gene set enrichment analysis and CIBERSORT analysis to determine its function and tumor-infiltrating immune cell proportion, respectively. The results revealed that the most abundant pathways among differentially expressed genes in LUAD primarily involved the cell cycle, ECM receptor interaction, protein digestion and absorption, p53 signaling pathway, complement and coagulation cascade, and tyrosine metabolism. Two ECM-associated subtypes were identified by consensus clustering. Besides, an ECM-related prognostic model was validated to predict LUAD survival, and it was associated with the tumor immune microenvironment. Additional cross-analysis screened laminin subunit beta 1 (LAMB1) for further research. The survival time of LUAD patients with elevated LAMB1 expression was longer than those with low LAMB1 expression. Gene set enrichment analysis and CIBERSORT analyses revealed that LAMB1 expression correlated with tumor immune microenvironment. In conclusion, a prognostic model of LUAD patients depending on the ECM receptor interaction pathway was constructed. Screening out LAMB1 can become a prognostic risk factor for LUAD patients or a potential target during LUAD treatment.

DDP Induced Cytotoxicity through miR-215-5p/COL5A1/FSTL1 Axis to Regulate Autophagy in Lung Adenocarcinoma Cells.

Cisplatin (DDP) resistance remains a major challenge in the treatment of lung adenocarcinoma (LUAD). Autophagy is an important mechanism to generate drug resistance. It has been established that COL5A1 has been shown to accelerate LUAD metastasis and affect cellular processes. We investigated the role of COL5A1 in DDP resistance using the H1299/DDP and A549/DDP cell lines. Flow cytometry, CCK8, and western blot assays were used to detect apoptosis, cell viability, and autophagy. In addition, upstream miRNAs were screened using bioinformatics methods. MS2-RIP assay and luciferase reporter gene assay were used to validate miRNA interaction with COL5A1. Transfection experiments and western blot experiments were performed to investigate miRNA targeting to COL5A1 and its regulation of autophagy through FSTL1. The role of miRNA and COL5A1 in LUAD cisplatin resistance was also verified in vivo. The down-regulation of COL5A1 significantly reduced the survival and autophagy of DDP-resistant cells while enhancing apoptosis. MiR-215-5p was found to be a direct regulator of COL5A1, which affects autophagy through FSTL1. The present study demonstrated that miR-215-5p regulated COL5A1 to modulate FSTL1 and autophagy, thereby attenuating LUAD resistance to DDP. These findings deepen the understanding of LUAD pathogenesis and provide potential insights into therapeutic strategies.

Unveiling the impact of cell death-related genes and immune dynamics on drug resistance in lung adenocarcinoma: a risk score model and functional insights

Lung adenocarcinoma (LUAD), characterized by its heterogeneity and complex pathogenesis, is the focus of this study which investigates the association between cell death-related genes and LUAD. Through machine learning, a risk score model was developed using the Coxboost rsf algorithm, demonstrating strong prognostic accuracy in both validation (GSE30219, GSE31210, GSE72094) and training (TCGA-LUAD) datasets with C-indices of 0.93, 0.67, 0.68, and 0.64, respectively. The study reveals that the expression of Keratin 18 (KRT18), a key cytoskeletal protein, varies across LUAD cell lines (DV-90, PC-9, A549) compared to normal bronchial epithelial cells (BEAS-2B), suggesting its potential role in LUAD's pathogenesis. Kaplan–Meier survival curves further validate the model, indicating longer survival in the low-risk group. A comprehensive analysis of gene expression, functional differences, immune infiltration, and mutations underscores significant variations between risk groups, highlighting the high-risk group's immunological dysfunction. This points to a more intricate tumor immune environment and the possibility of alternative therapeutic strategies. The study also delves into drug sensitivity, showing distinct responses between risk groups, underscoring the importance of risk stratification in treatment decisions for LUAD patients. Additionally, it explores KRT18's epigenetic regulation and its correlation with immune cell infiltration and immune regulatory molecules, suggesting KRT18's significant role in the tumor immune landscape. This research not only offers a valuable prognostic tool for LUAD but also illuminates the complex interplay between cell death-related genes, drug sensitivity, and immune infiltration, positioning KRT18 as a potential therapeutic or prognostic target to improve patient outcomes by personalizing LUAD treatment strategies.

A scoring model for the expression of genes related to programmed cell death predicts immunotherapy response and prognosis in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) continues to be the leading cause of cancer death worldwide, driven by environmental factors like smoking and genetic predispositions. LUAD has a high mortality rate, and new biomarkers are urgently needed to improve treatment strategies and patient management. Programmed cell death (PCD) is involved in tumor progression and response to treatment. Therefore, there is a need for an extensive study of the role and functions of PCD-related genes (PCDRGs) in lung adenocarcinoma so as to understand the pathophysiologic features of lung adenocarcinoma.MethodsBased on TCGA and GEO databases, this research is aimed at screening differentially expressed PCD-related genes in lung adenocarcinoma. We conducted GO, and KEGG analysis to establish the link between these genes and biological processes. By applying various machine learning algorithms such as CoxBoost analysis, we developed PCD-related indices (PCDI) that were used to verify their ability to predict prognosis with the use of other datasets. This was done in addition to exploring the biological functions of PCD genes associated with lung adenocarcinoma by assessing the relationship between immune cell components of tumor microenvironment and PCD genes together with examining how they affect drug sensitivity.ResultsThe research presented in this article offers significant insights into LUAD. The authors identified 113 PCDRGs that were differentially expressed in LUAD. These genes are implicated in various biological functions, including High risk ing apoptosis, ferroptosis, and pathways specific to non-small cell lung cancer. Notably, the PCDI proved effective in distinguishing between High risk and Low risk LUAD patients, demonstrating a higher accuracy in prognosis prediction compared to traditional clinical indicators such as age and gender. This high prediction accuracy was validated in both test and validation cohorts. Additionally, these genes showed significant correlations with immune cell infiltration and drug sensitivity in LUAD patients.ConclusionWe analysed the expression and function of PCDRGs in LUAD and revealed their correlation with patient survival, the immune microenvironment and drug sensitivity. The constructed PCDI model provides a scientific basis for the personalised treatment of lung adenocarcinoma, and future optimisation of treatment strategies based on these genes may improve patient clinical outcomes.

Radiomics-Based Support Vector Machine Distinguishes Molecular Events Driving the Progression of Lung Adenocarcinoma

IntroductionAn increasing number of early-stage lung adenocarcinomas (LUAD) are detected as lung nodules. The radiological features related to LUAD progression warrant further investigation. Exploration is required to bridge the gap between radiomics-based features and molecular characteristics of lung nodules. MethodsConsensus clustering was applied to the radiomic features of 1212 patients to establish stable clustering. Clusters were illustrated using clinicopathological and next-generation sequencing. A classifier was constructed to further investigate the molecular characteristics in patients with paired computed tomography and RNA sequencing data. ResultsPatients were clustered into four clusters. Cluster 1 was associated with a low consolidation-to-tumor ratio, preinvasion, grade I disease, and good prognosis. Clusters 2 and 3 reported increasing malignancy with a higher consolidation-to-tumor ratio, higher pathologic grade, and poor prognosis. Cluster 2 possessed more spread through air spaces and cluster 3 reported a higher proportion of pleural invasion. Cluster 4 had similar clinicopathological features as cluster 1 except but a proportion of grade II disease. RNA sequencing indicated that cluster 1 represented nodules with indolent growth and good differentiation, whereas cluster 4 reported progression in cell development but still had low proliferative activity. Nodules with high proliferation were classified into clusters 2 and 3. In addition, the radiomics classifier distinguished cluster 2 as nodules harboring an activated immune environment, whereas cluster 3 represented nodules with a suppressive immune environment. Furthermore, signatures associated with the prognosis of early-stage LUAD were validated in external datasets. ConclusionsRadiomics features can manifest molecular events driving the progression of LUAD. Our study provides molecular insight into radiomics features and assists in the diagnosis and treatment of early-stage LUAD.

Prognostic model of lung adenocarcinoma based on immunoprognosis-related genes and related drug prediction.

Lung cancer (LC) is the most common malignant tumor in the world, and lung adenocarcinoma (LUAD) is the most common type of LC. Immune microenvironment plays a critical role in cancer from onset to relapse. We aimed to identify an effective immune-related prediction model for assessing prognosis and predicting the relevant tumor therapeutic drugs. According to the RNA sequencing data of LUAD transcriptome in The Cancer Genome Atlas (TCGA) database and the immune-related genes obtained from IMMPORT (The Immunology Database and Analysis Portal) database, immune prognosis-related genes were screened. Weighted gene co-expression network analysis (WGCNA) identified hub genes in differentially expressed immune-related genes (DEIRGs). Least absolute shrinkage and selection operator (LASSO) Cox and ten rounds of cross-validation were used to screen core genes to establish a prognostic model, and in situ hybridization was used to verify the expression of core genes in LUAD. Then the patients from the TCGA database were divided into high-risk group and low-risk group. The survival, tumor microenvironment (TME) and immune cell infiltration of different groups were further analyzed, and the differential genes between the two groups were analyzed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) enrichment analyses. Finally, the small molecular drugs that can inhibit the prognosis of LUAD were screened by Connectivity Map (CMAP), and the therapeutic mechanism of small molecular drug oxibendazole was verified by Cell Counting Kit-8 (CCK-8) experiment. A four-immunoprognosis-related gene model was established to forecast the overall survival (OS) of LUAD through LASSO Cox regression and ten rounds of cross-validation analysis. This prognostic model stratified LUAD patients into low-risk and high-risk groups. According to the findings of the survival analysis, the low-risk group had a greater OS than the high-risk group and the content of immune cells in LUAD was corrected with the survival prognosis of patients. Univariate and multivariate Cox regression also revealed that the prognostic model was an independent prognosis factor in LUAD. Five kinds of small molecular drugs which can inhibit the prognosis of LUAD were screened by CMAP. As shown by CCK-8 test, the small molecular drug "oxibendazole" can effectively inhibit the proliferation of LUAD cells. Based on immune-related prognostic genes, a new prognostic model for LUAD was constructed. Oxibendazole can inhibit the proliferation of LUAD cells, which provides a new idea for the treatment of LUAD.

Functional elucidation of the EIF4A3–circR-4225–miR-507–TNFSF11 regulatory axis in LUAD and its role in tumor progression

Lung adenocarcinoma (LUAD) is the most common subtypes of NSCLC. However, the therapeutic effects for LUAD are unsatisfactory at current stage, so it is important to find new molecular targets and therapeutic strategies. circRNAs can regulate the expression of target genes by binding to microRNAs (miRNAs) to form competitive endogenous RNAs (ceRNAs). Therefore, we investigated the functions of circR-4225 in the tumor progression of LUAD and its molecular mechanism in this paper. circR-4225 is up-regulated in LUAD tissues. EIF4A3, a member of the eukaryotic translation initiation factor 4A (EIF4A) family, promotes the expression of circR-4225. circR-4225 acts as a molecular sponge to down-regulate miR-507, which promotes the up-regulation of the expression of its target gene–tumor necrosis factor superfamily member 11 (TNFSF11). Knockdown of circR-4225 in the LUAD cell lines can inhibit cell proliferation and viability, and promote apoptosis of the LUAD cell lines, which can be reverted by inhibiting miR-507 or overexpressing TNFSF11. To sum it up, this study demonstrated that circR-4225 was significantly up-regulated in LUAD tissues, and circR-4225 promoted LUAD progression by sponging miR-507 and up-regulating TNFSF11. This study can provide new molecular targets for early diagnosis and treatment of LUAD.

LncRNA MALAT-1 modulates EGFR-TKI resistance in lung adenocarcinoma cells by downregulating miR-125

Molecular targeted therapy resistance remains a major challenge in treating lung adenocarcinoma (LUAD). The resistance of Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitor) plays a dominant role in molecular targeted therapy. Our previous research demonstrated the role of MALAT-1 (Metastasis-associated lung adenocarcinoma transcript 1) in the formation of Erlotinib-resistant LUAD cells. This study aims to uncover the mechanism of MALAT-1 overexpression in Erlotinib-resistant LUAD cells. The RT2 LncRNA PCR array system was used to explore MALAT-1 regulation in Erlotinib-resistant LUAD cells through patient serum analysis. Dual luciferase reporter experiments confirmed the binding between MALAT-1 and miR-125, leading to regulation of miR-125 expression. Functional assays were performed to elucidate the impact of MALAT1 on modulating drug resistance, growth, and Epithelial-mesenchymal transition (EMT, Epithelial-mesenchymal transition) in both parental and Erlotinib-resistant LUAD cells. The investigation unveiled the mechanism underlying the competing endogenous RNA (ceRNA, competing endogenouse RNA) pathway. MALAT1 exerted its regulatory effect on miR-125 as a competing endogenous RNA (ceRNA). Moreover, MALAT1 played a role in modulating the sensitivity of LUAD cells to Erlotinib. Rab25 was identified as the direct target of miR-125 and mediated the functional effects of MALAT1 in Erlotinib-resistant LUAD cells. In conclusion, our study reveals overexpress MALAT-1 cause the drug resistance of EGFR-TKIs in non-small cell lung cancer (NSCLC) through the MALAT-1/miR-125/Rab25 axis. These findings present a potential novel therapeutic target and perspective for the treatment of LUAD.