scholarly journals Multi-omics integrative analysis and survival risk model construction of non-small cell lung cancer based on The Cancer Genome Atlas datasets

2020 ◽  
Author(s):  
Mingyuan Luan ◽  
Fucheng Song ◽  
Shuyuan Qu ◽  
Xi Meng ◽  
Junjie Ji ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Risk Model ◽  
Small Cell ◽  
The Cancer Genome Atlas ◽  
Small Cell Lung ◽  
Cancer Genome Atlas ◽  
Survival Risk ◽  
Genome Atlas

RORγ agonist LYC-55716, a novel small molecule immunotherapy: Rationale for clinical evaluation in non-small cell lung cancer based on translational and bioinformatic evaluation.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 171-171
Author(s):  
Laura Carter ◽  
Xikui Liu ◽  
Hongxiu Li ◽  
Elizabeth Zawidzka ◽  
Yilin Gao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cell Formation ◽  
Small Cell ◽  
The Cancer Genome Atlas ◽  
Orphan Receptor ◽  
Small Cell Lung

171 Background: Retinoic acid receptor–related orphan receptor γ (RORγ) agonists modulate immune cell gene expression to enhance effector function and decrease regulatory T cell formation and expression of checkpoint pathways. RORγ agonists have demonstrated antitumor activity in syngeneic tumor models. Translational and bioinformatic assessments were conducted to support inclusion of patients with non–small-cell lung cancer (NSCLC) in a Phase 2a expansion of clinical trial LYC-55716-1001 (NCT02929862). Methods: The Cancer Genome Atlas (TCGA) NSCLC dataset was evaluated for (a) expression of RORγ and RORγ-inducing cytokines and correlation with survival; (b) genes related to RORγ biology, biomarkers of endogenous RORγ agonists; and (c) tumor microenvironment (TME) immune profiles. RORγ expression and the in vitro effects of a RORγ agonist on peripheral blood mononuclear cells (PBMCs) from lung adenocarcinoma (LA) and squamous cell carcinoma (SCC) patients were assessed. Results: In TCGA, 25% of NSCLC tumors expressed moderate/high levels of RORγ, suggesting infiltration of Type 17 cells. There was a statistically significant correlation between high RORγ expression and improved survival in LA patients. Genes that support Type 17 cell formation (IL1B, IL23A, IL6) were expressed in ~50% of tumors. RORγ expression was confirmed in PBMCs isolated from LA and SCC patients. Analysis of TCGA data and patient samples identified low expression of sterol efflux and uptake genes, suggesting low levels of endogenous RORγ agonist in TME. In TCGA, high mutational burden and high expression of immune-related genes were found in NSCLC tumors. RORγ agonist treatment of PBMCs from LA and SCC patients increased IL-17A and IL-26 (LA and SCC) and decreased PD1 (LA). In Phase 1 clinical testing, LYC-55716 has been well tolerated, demonstrating long-term disease stabilization in heavily pretreated patients. Conclusions: Bioinformatic analyses of RORγ expression/biology, correlation with improved survival, plus in vitro findings support inclusion of NSCLC in an ongoing Phase 2 clinical trial of LYC-55716.

scholarly journals A Multi-Omics Network of a Seven-Gene Prognostic Signature for Non-Small Cell Lung Cancer

2021 ◽  
Vol 23 (1) ◽  
pp. 219
Author(s):  
Qing Ye ◽  
Brianne Falatovich ◽  
Salvi Singh ◽  
Alexey V. Ivanov ◽  
Timothy D. Eubank ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Transcriptional Regulatory Network ◽  
Early Stage ◽  
Recurrence Risk ◽  
Small Cell ◽  
The Cancer Genome Atlas ◽  
Small Cell Lung ◽  
Western Blots

There is an unmet clinical need to identify patients with early-stage non-small cell lung cancer (NSCLC) who are likely to develop recurrence and to predict their therapeutic responses. Our previous study developed a qRT-PCR-based seven-gene microfluidic assay to predict the recurrence risk and the clinical benefits of chemotherapy. This study showed it was feasible to apply this seven-gene panel in RNA sequencing profiles of The Cancer Genome Atlas (TCGA) NSCLC patients (n = 923) in randomly partitioned feasibility-training and validation sets (p < 0.05, Kaplan–Meier analysis). Using Boolean implication networks, DNA copy number variation-mediated transcriptional regulatory network of the seven-gene signature was identified in multiple NSCLC cohorts (n = 371). The multi-omics network genes, including PD-L1, were significantly correlated with immune infiltration and drug response to 10 commonly used drugs for treating NSCLC. ZNF71 protein expression was positively correlated with epithelial markers and was negatively correlated with mesenchymal markers in NSCLC cell lines in Western blots. PI3K was identified as a relevant pathway of proliferation networks involving ZNF71 and its isoforms formulated with CRISPR-Cas9 and RNA interference (RNAi) profiles. Based on the gene expression of the multi-omics network, repositioning drugs were identified for NSCLC treatment.

scholarly journals Tumor suppressor properties of the small C-terminal domain phosphatases in non-small cell lung cancer

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
George S. Krasnov ◽  
Grigory A. Puzanov ◽  
Marina A. Afanasyeva ◽  
Erdem B. Dashinimaev ◽  
Khava S. Vishnyakova ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Active Form ◽  
Small Cell ◽  
The Cancer Genome Atlas ◽  
Mrna Levels ◽  
Small Cell Lung ◽  
Terminal Domain

Abstract Non-Small Cell Lung Cancer (NSCLC) is responsible for the majority of deaths caused by cancer. Small C-terminal domain (CTD) phosphatases (SCP), CTDSP1, CTDSP2 and CTDSPL (CTDSPs) belong to SCP/CTDSP subfamily and are involved in many vital cellular processes and tumorigenesis. High similarity of their structures suggests similar functions. However their role in NSCLC remains insufficiently understood. For the first time we revealed the suppressor function of CTDSPs leading to a significant growth slowdown and senescence of A549 lung adenocarcinoma (ADC) cells in vitro. Their tumor-suppressive activity can be realized through increasing the proportion of the active form of Rb protein dephosphorylated at Ser807/811, Ser780, and Ser795 (P&lt;0.05) thereby negatively regulating cancer cell proliferation. Moreover, we observed that a frequent (84%, 39/46) and highly concordant (Spearman’s rank correlation coefficient (rs) = 0.53–0.62, P≤0.01) down-regulation of CTDSPs and RB1 is characteristic of primary NSCLC samples (n=46). A clear difference in their mRNA levels was found between lung ADCs with and without lymph node metastases, but not in squamous cell carcinomas (SCCs) (P≤0.05). Based on The Cancer Genome Atlas (TCGA) data and the results obtained using the CrossHub tool, we suggest that the well-known oncogenic cluster miR-96/182/183 could be a common expression regulator of CTDSPs. Indeed, according to our qPCR, the expression of CTDSPs negatively correlates with these miRs, but positively correlates with their intronic miR-26a/b. Our results reflect functional association of CTDSP1, CTDSP2, and CTDSPL, expand knowledge about their suppressor properties through Rb dephosphorylation and provide new insights into the regulation of NSCLC growth.

scholarly journals Ferroptosis-related gene AKR1C1 predicts the prognosis of non-small cell lung cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fangfang Huang ◽  
Yushi Zheng ◽  
Xiaoling Li ◽  
Hui Luo ◽  
Lianxiang Luo
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
The Cancer Genome Atlas ◽  
Nsclc Cell ◽  
Related Gene ◽  
Small Cell Lung ◽  
Data Set

Abstract Background Ferroptosis is a newly discovered mode of cell death distinct from apoptosis and necrosis, and its activation contributes to anticancer therapy in a variety of cancers. However, the prognostic value of ferroptosis-related genes in non-small cell lung cancer (NSCLC) remains to be further investigated. Methods NSCLC transcriptome mRNA-seq data set and corresponding clinical data set were downloaded from the Cancer Genome Atlas (TCGA). Then, bioinformatics approaches were subsequently employed to identify potential prognostic markers. Finally, the effects of candidate markers on NSCLC cell proliferation, migration, and ferroptosis were assessed by CCK8, colony formation, wound-healing assay, and functional assays related to ferroptosis. Results A total of 37 common differentially expressed genes were screened based TCGA database. Six overall survival associated genes (ENPP2, ULK1, CP, LURAP1L, HIC1, AKR1C1) were selected to build survival model, of which hub gene AKR1C1 was with high expression and low ferroptosis level in NSCLC tumor. Further research showed that AKR1C1 was related with many pathways involved in the process of ferroptosis and associated with diverse cancer-infiltrating immune cells. Moreover, the results of in vitro experiments indicated that the expression of AKR1C1 was upregulated in NSCLC cell lines, and silencing AKR1C1 can inhibit the proliferation and migration of NSCLC cells and promote the occurrence of ferroptosis. Conclusions Our study revealed the potential role of ferroptosis-related gene AKR1C1 in NSCLC, which can be used for prognostic prediction in NSCLC.

scholarly journals Seven Autophagy-Related Genes are Associated with the Tumor Immune Microenvironment in Predicting Survival Risk of Non-Small Cell Lung Cancer

2021 ◽  
Author(s):  
Huihui Jiang ◽  
Aiqun Xu ◽  
Min Li ◽  
Rui Han ◽  
Enze Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Survival Analysis ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Risk Model ◽  
Cox Regression ◽  
Small Cell ◽  
Gene Set Enrichment Analysis ◽  
Small Cell Lung

Abstract Background: Non-small cell lung cancer (NSCLC) ranks first among global cancer-related deaths. Despite the emergence of various immunological and targeted therapies, immune tolerance remains a barrier to treatment. Methods: It has been found that this obstacle can be overcome by targeting autophagy-related genes (ATGs). ATGs were screened by coexpression analysis and the genes related to the prognosis of lung cancer were screened using Kaplan–Meier (K-M) survival analysis, univariate Cox regression, and multivariate Cox regression. The prognostic risk model of ATGs was constructed and verified using K-M survival analysis and receiver operating characteristic (ROC) curve analysis. Results: The prognostic risk model of ATGs was constructed. Gene set enrichment analysis (GSEA) showed that the function and pathway of ATG enrichment were closely related to immune cell function. CIBERSORT, LM22 matrix, and Pearson correlation analysis showed that risk signals were significantly correlated with immune cell infiltration and immune checkpoint genes. Conclusions: We identified and independently verified the ATG (AL691432.2, MMP2-AS1, AC124067.2, CRNDE, ABALON, AL161431.1, NKILA) in NSCLC patients and found that immune regulation in the tumor microenvironment is closely related to this gene.

scholarly journals MiR-516a-5p inhibits the proliferation of non-small cell lung cancer by targeting HIST3H2A

2019 ◽  
Vol 33 ◽  
pp. 205873841984148 ◽  
Author(s):  
Xiang-Yun Ye ◽  
Ling Xu ◽  
Shun Lu ◽  
Zhi-Wei Chen
Keyword(s):  
Lung Cancer ◽  
Prognostic Factor ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Recurrence ◽  
Small Cell ◽  
Independent Prognostic Factor ◽  
The Cancer Genome Atlas ◽  
Small Cell Lung ◽  
Data Set

The dysregulation of microRNAs (miRNAs) is associated with the pathogenesis of non-small cell lung cancer (NSCLC). However, the mechanisms by which miR-516a-5p contributes to NSCLC remain unclear. The association between miR-516a-5p expression and the clinicopathological characteristics and prognosis in patients with NSCLC was analyzed by The Cancer Genome Atlas (TCGA) data set. The targets of miR-516a-5p were identified by bioinformatic analysis and luciferase report assay. MTT and soft agar assays were conducted to investigate the function of miR-516a-5p in NSCLC cells. We found that the expression of miR-516a-5p was decreased in NSCLC tissues and associated with the age, pathological stage, and tumor size, acting as an independent prognostic factor of tumor recurrence in patients with NSCLC. Restoration of miR-516a-5p inhibited the cell viability and anchorage-independent growth of NSCLC cells, but its inhibitor had the opposite effects. Histone cluster 3 H2A (HIST3H2A) was further identified as a direct target of miR-516a-5p and displayed a negative correlation with miR-516a-5p expression in NSCLC tissues. Overexpression of HIST3H2A reversed the anti-proliferation effects induced by miR-516a-5p and acted as an independent prognostic factor of poor survival in patients with NSCLC. Altogether, our findings demonstrate that miR-516a-5p may function as a tumor suppressive factor in NSCLC cells by targeting HIST3H2A and might represent a potential indicator of tumor recurrence in patients with NSCLC.

COL1A1 is a potential prognostic marker and therapeutic target in non-small cell lung cancer.

2022 ◽  
Vol 17 ◽  
Author(s):  
Boyu Pan ◽  
Chen Huang ◽  
Yafei Xia ◽  
Cuicui Zhang ◽  
Bole Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Prognostic Marker ◽  
Cell Lung Cancer ◽  
Therapeutic Target ◽  
Small Cell ◽  
The Cancer Genome Atlas ◽  
Small Cell Lung ◽  
Kegg Pathways ◽  
Nsclc Patients

Background: Nowadays, non-small cell lung cancer (NSCLC) is a common and highly fatal malignancy in worldwide. Therefore, to identify the potential prognostic markers and therapeutic targets is urgent for patients. Objective: This study aims to find hub targets associated with NSCLC using multiple databases. Methods: Differentially expressed genes (DEGs) from Genome Expression Omnibus (GEO) cohorts were employed for the enrichment analyses of Gene Ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genome (KEGG) pathways. Candidate key genes, filtered from the topological parameter 'Degree' and validated using the The Cancer Genome Atlas (TCGA) cohort, were analyzed for their association with clinicopathological features and prognosis of NSCLC. Meanwhile, immunohistochemical cohort analyses and biological verification were further evaluated. Results: A total of 146 DEGs were identified following data preprocessing, and a protein-protein interaction (PPI) systematic network was constructed based on them. The top ten candidate core genes were further extracted from the above PPI network by using 'Degree' value, among which COL1A1 was shown to associate with overall survival (OS) of NSCLC as determined by using the Kaplan-Meier analysis (p=0.028), and could serve as an independent prognostic factor for OS in NSCLC patients (HR, 0.814; 95% CI, 0.665-0.996; p=0.046). We then analyzed the clinical stages, PPI, mutations, potential biological functions and immune regulations of COL1A1 in NSCLC patients using multiple bioinformatics tools, including GEPIA, GeneMANIA, cBioPortal, GESA and TISIDB. Finally, we further experimentally validated the overexpression of COL1A1 in NSCLC samples, and found that inhibition of COL1A1 expression moderately sensitized NSCLC cells to cisplatin. Conclusion: Thus, our results show that COL1A1 may serve as a potential prognostic marker and therapeutic target in NSCLC.

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