Circular RNA circABCC4 regulates lung adenocarcinoma progression via miR-3186-3p/TNRC6B axis

Lung adenocarcinoma (LUAD), a general kind of bronchogenic malignancy globally, is depicted as one of the most critical factors affecting human health severely. Featured with loop structure, circular RNA (circRNA) has been described as an essential regulator of multiple human malignancies. Nevertheless, knowledge concerning the regulatory function of circRNA in LUAD progression remains limited. Identified as a novel circRNA, circABCC4 has not been studied in LUAD as yet. This is the first time to probe into the underlying role of circABCC4 in LUAD. In this study, a notably elevated expression of circABCC4 was found in LUAD tissues and cells. Besides, circABCC4 is verified to be characterized with a circular structure in LUAD. Functional assays elucidated that knockdown of circABCC4 significantly impaired LUAD cell proliferation, migration as well as accelerated cell apoptosis. Molecular mechanism experiments later revealed that circABCC4 could bind with miR-3186-3p and miR-3186-3p was a tumor suppressor in LUAD. Moreover, TNRC6B was validated to combine with miR-3186-3p, and its expression was respectively negatively and positively regulated by miR-3186-3p and circABCC4 in LUAD. Final rescue experiments further delineated that TNRC6B upregulation partially restored circABCC4 downregulation-mediated effect on LUAD progression. In sum, circABCC4 regulates LUAD progression via miR-3186-3p/TNRC6B axis.     

Exploration of the prognostic prediction value of the PANoptosis-based risk score and its correlation with tumor immunity in lung adenocarcinoma

Lung adenocarcinoma (LUAD) is a common cancer with high mortality worldwide. PANoptosis is a novel inflammatory programmed cell death modality with the characteristics of pyroptosis, apoptosis and necroptosis. It is necessary to explore PANoptosis-related genes in LUAD patients and offer evidence for prognosis prediction and therapeutic strategies. Single-cell RNA sequencing data and RNA expression profiles of LUAD patients from The Cancer Genome Atlas and Gene Expression Omnibus databases are used to screen PANoptosis-related differential genes for the construction of a risk model. Fifteen PANoptosis-related markers with prognostic value were identified by Least Absolute Shrinkage and Selection Operator (LASSO)–Cox regression analysis. Kaplan–Meier analysis and receiver operating characteristic curve analysis further demonstrated the significant predictive capability. Immune infiltration, Single Nucleotide Variants (SNV) mutations, and clinical drug susceptibility were analyzed. In conclusion, a risk model of 15 PANoptosis-related genes has significant value in prognostic prediction for LUAD and has potential to direct clinical therapeutic strategies during the treatment.     

The increased expression and aberrant methylation of SHC1 in non–small cell lung cancer: Integrative analysis of clinical and bioinformatics databases

Despite the previous evidence showing that SHC adaptor protein 1 (SHC1) could encode three distinct isoforms (p46SHC, p52SHC and p66SHC) that function in different activities such as regulating life span and Ras activation, the precise underlying role of SHC1 in lung cancer also remains obscure. In this study, we firstly found that SHC1 expression was up-regulated both in lung adenocarcinoma (LUAD) and in lung squamous cell carcinoma (LUSC) tissues. Furthermore, compared to patients with lower SHC1 expression, LUAD patients with higher expression of SHC1 had poorer overall survival (OS). Moreover, higher expression of SHC1 was also associated with worse OS in patients with stages 1 and 2 but not stage 3 lung cancer. Significantly, the analysis showed that SHC1 methylation level was associated with OS in lung cancer patients. It seemed that the methylation level at specific probes within SHC1 showed negative correlations with SHC1 expression both in LUAD and in LUSC tissues. The LUAD and LUSC patients with hypermethylated SHC1 at cg12473916 and cg19356022 probes had a longer OS. Therefore, it is reasonable to conclude that SHC1 has a potential clinical significance in LUAD and LUSC patients.     

CLEC10A is a prognostic biomarker and correlated with clinical pathologic features and immune infiltrates in lung adenocarcinoma

CLEC10A, (C-type lectin domain family 10, member A), as the member of C-type lectin receptors (CLRs), plays a vital role in modulating innate immunity and adaptive immunity and has shown great potential as an immunotherapy target for cancers. However, there is no functional research of CLEC10A in prognostic risk, immunotherapy or any other treatment of lung adenocarcinoma (LUAD). We performed bioinformatics analysis on LUAD data downloaded from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus), and jointly analysed with online databases such as HPA, LinkedOmics, TIMER, ESTIMATE and TISIDB. We found that lower expression of CLEC10A was accompanied with worse outcomes of LUAD patients. Moreover, CLEC10A expression was significantly correlated with a variety of the tumour-infiltrating immune cells (TIICs). As a promising prognosis predictor and potential immunotherapy target, the potential influence and mechanisms of CLEC10A in LUAD deserve further exploring.     

DNA methylation profiling to predict recurrence risk in stage Ι lung adenocarcinoma: Development and validation of a nomogram to clinical management

Increasing evidence suggested DNA methylation may serve as potential prognostic biomarkers; however, few related DNA methylation signatures have been established for prediction of lung cancer prognosis. We aimed at developing DNA methylation signature to improve prognosis prediction of stage I lung adenocarcinoma (LUAD). A total of 268 stage I LUAD patients from the Cancer Genome Atlas (TCGA) database were included. These patients were separated into training and internal validation datasets. GSE39279 was used as an external validation set. A 13‐DNA methylation signature was identified to be crucially relevant to the relapse‐free survival (RFS) of patients with stage I LUAD by the univariate Cox proportional hazard analysis and the least absolute shrinkage and selection operator (LASSO) Cox regression analysis and multivariate Cox proportional hazard analysis in the training dataset. The Kaplan‐Meier analysis indicated that the 13‐DNA methylation signature could significantly distinguish the high‐ and low‐risk patients in entire TCGA dataset, internal validation and external validation datasets. The receiver operating characteristic (ROC) analysis further verified that the 13‐DNA methylation signature had a better value to predict the RFS of stage I LUAD patients in internal validation, external validation and entire TCGA datasets. In addition, a nomogram combining methylomic risk scores with other clinicopathological factors was performed and the result suggested the good predictive value of the nomogram. In conclusion, we successfully built a DNA methylation‐associated nomogram, enabling prediction of the RFS of patients with stage I LUAD.     

CircFAT1 Promotes Lung Adenocarcinoma Progression by Sequestering miR-7 from Repressing IRS2-ERK-mediated CCND1 Expression

Our understanding of coding gene functions in lung cancer leads to the development of multiple generations of targeted drugs. Noncoding RNAs, including circular RNAs (circRNAs), have been demonstrated to play a vital role in tumorigenesis. Uncovering the functions of circRNAs in tumorigenesis and their underlying regulatory mechanisms may shed new light on the development of novel diagnostic and therapeutic strategies for human cancer. Here we report the important role of circFAT1 in lung adenocarcinoma (LUAD) progression and the potential impact of circFAT1 on LUAD treatment. We found that circFAT1 was one of the top expressed circRNAs in A549 cells by circRNA-seq and was significantly upregulated in human LUAD tissues. Multiple cellular assays with A549 and PC9 LAUD cell lines under both gain-of-function and loss-of-function conditions demonstrated that circFAT1 promoted proliferation of LUAD cells in vitro and in vivo. At molecular level, circFAT1 sequestered miR-7 to upregulate IRS2, which in turn regulated downstream ERK1/2 phosphorylation and CCND1 expression, ultimately promoting tumor progression. In addition, we showed that DDP treatment was much more effective in circFAT1 knockdown tumor cells in vitro and in a xenograft tumor model. Our results indicate that circFAT1 promote tumorigenesis in LUAD through sequestering miR-7, consequently upregulating IRS2-ERK1/2-mediated CCND1 expression, and can be a valuable therapeutic target and an important parameter for precision treatment in LUAD patients.     

Exploring and comparing of the gene expression and methylation differences between lung adenocarcinoma and squamous cell carcinoma

Lung cancer is one of the most frequently diagnosed malignant tumors and the main reason for cancer-related death around the world, whereas nonsmall cell lung cancer that consists two subtypes: lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) is responsible for an estimated 85% of all lung cancers. The current study aimed to explore gene expression and methylation differences between LUAD and LUSC. EdgeR was used to identify differentially regulated genes between normal and cancer in the LUAD and LUSC extracted from The Cancer Genome Atlas (TCGA), respectively, whereas SAM was used to find genes with differential methylation between normal and cancer in the LUAD and LUSC, respectively. Finally, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed to analyze the function which these genes enriched in. A total of 391 genes with opposite methylation patterns in LUAD and LUSC and four functional pathways were obtained (false discovery rate (FDR) < 0.1). These pathways mainly included fat digestion and absorption, phenylalanine metabolism, bile secretion, and so on, which were related to the airframe nutrition metabolic pathway. Moreover, two genes CTSE (cathepsin E) and solute carrier family 5 member 7 (SLC5A7) were also found, among which CTSE was overexpressed and hypomethylated in LUAD corresponding to normal lung tissues, whereas SLC5A7 showed the opposite in LUAD. In conclusion, this study investigated the differences between the gene expression and methylation patterns in LUAD and LUSC, and explored their different biological characteristics. Further understanding of these differences may promote the discovery and development of new, accurate strategies for the prevention, diagnosis, and treatment of lung cancer.