PurposeThis study aimed to explore the circular RNA (circRNA/circ) profile engaged in non-small cell lung cancer (NSCLC) development and metastasis and to investigate potentially key carcinogenic circRNAs related to NSCLC.MethodsCircRNA profiles between 10 NSCLC tissues and 10 adjacent tissues and between five NSCLC tissues with lymph node metastasis (LNM) and five NSCLC tissues without LNM were detected by Arraystar Human circRNA Array followed by bioinformatics. Circ_0008594 knockdown, circ_0004293 overexpression, and circ_0003832 overexpression plasmids were transfected into H23 and H460 cells to sort potential oncogenic circRNA. Then circ_0008594 overexpression and knockdown plasmids were transfected, followed by that circ_0008594 knockdown plus miR-760 knockdown plasmids were transfected into these cells. Cell proliferation, apoptosis, invasion, stemness, and pathways were detected. In addition, xenograft mice models were constructed via injecting H23 cells with circ_0008594 overexpression or knockdown to validate the findings.ResultsA total of 455 dysregulated circRNAs in NSCLC tissues versus adjacent tissues and 353 dysregulated circRNAs in NSCLC tissues with LNM versus those without LNM were discovered. Via cross-analysis, 19 accordant circRNAs were uncovered, among which three candidate circRNAs (circ_0008594, circ_0004293, circ_0003832) were chosen for functional experiments, during which it was observed that circ_0008549 affected H23 and H460 cell proliferation and apoptosis more obviously than circ_0004293 and circ_0003832. Subsequent experiments showed that circ_0008594 promoted H23 and H460 cell proliferation and invasion but affected stemness less and negatively regulated miR-760 via direct binding. Furthermore, miR-760 attenuated the effect of circ_0008549 on regulating H23 and H460 cell functions and the PI3K/AKT and MEK/ERK pathways. In vivo experiments further confirmed that circ_0008549 increased tumor volume, epithelial-mesenchymal transition, and the PI3K/AKT and MEK/ERK pathways while reducing tumor apoptosis and miR-760 NSCLC xenograft models.ConclusionOur study identifies several valuable circRNAs related to NSCLC development and LNM. Furthermore, as a key functional circRNA, circ_0008594 was observed to promote NSCLC progression by regulating the miR-760-mediated PI3K/AKT and MEK/ERK pathways.
Background Field cancerization is the process in which a population of normal or pre-malignant cells is affected by oncogenic alterations leading to progressive molecular changes that drive malignant transformation. Aberrant DNA methylation has been implicated in early cancer development in non-small cell lung cancer (NSCLC); however, studies on its role in field cancerization (FC) are limited. This study aims to identify FC-specific methylation patterns that could distinguish between pre-malignant lesions and tumor tissues in NSCLC. Methods We enrolled 52 patients with resectable NSCLC and collected resected tumor (TUM), tumor-adjacent (ADJ) and tumor-distant normal (DIS) tissue samples, among whom 36 qualified for subsequent analyses. Methylation levels were profiled by bisulfite sequencing using a custom lung-cancer methylation panel. Results ADJ and DIS samples demonstrated similar methylation profiles, which were distinct from distinct from that of TUM. Comparison of TUM and DIS profiles led to identification of 1740 tumor-specific differential methylated regions (DMRs), including 1675 hypermethylated and 65 hypomethylated (adjusted P < 0.05). Six of the top 10 tumor-specific hypermethylated regions were associated with cancer development. We then compared the TUM, ADJ, and DIS to further identify the progressively aggravating aberrant methylations during cancer initiation and early development. A total of 332 DMRs were identified, including a predominant proportion of 312 regions showing stepwise increase in methylation levels as the sample drew nearer to the tumor (i.e. DIS < ADJ < TUM) and 20 regions showing a stepwise decrease pattern. Gene set enrichment analysis (GSEA) for KEGG and GO terms consistently suggested enrichment of DMRs located in transcription factor genes, suggesting a central role of epigenetic regulation of transcription factors in FC and tumorigenesis. Conclusion We revealed distinct methylation patterns between pre-malignant lesions and malignant tumors, suggesting the essential role of DNA methylation as an early step in pre-malignant field defects. Moreover, our study also identified differentially methylated genes, especially transcription factors, that could potentially be used as markers for lung cancer screening and for mechanistic studies of FC and early cancer development.
Background: Thymic epithelial tumors (TETs), originating from the thymic epithelial cells, are the most common primary neoplasms of the anterior mediastinum. Emerging evidence demonstrated that the competing endogenous RNAs (ceRNAs) exerted a crucial effect on tumor development. Hence, it is urgent to understand the regulatory mechanism of ceRNAs in TETs and its impact on tumor prognosis. Methods: TETs datasets were harvested from the UCSC Xena as the training cohort, followed by differentially expressed mRNAs (DEmRNAs), lncRNAs (DElncRNAs), and miRNAs (DEmiRNAs) at different pathologic type (A, AB, B, and TC) identified via DESeq2 package. clusterProfiler package was utilized to carry out gene ontology and Kyoto encyclopedia of genes and genomes functional analysis on the DEmRNAs. Subsequently, the lncRNA-miRNA-mRNA regulatory network was constructed to screen the key DEmRNAs. After the key DEmRNAs were verified in the external cohort from Gene Expression Omnibus database, their associated-ceRNAs modules were used to perform the K-M and Cox regression analysis to build a prognostic significance for TETs. Lastly, the feasibility of the prognostic significance was validated by receiver operating characteristic (ROC) curves and the area under the curve. Results: Finally, a total of 463 DEmRNAs, 87 DElncRNAs, and 20 DEmiRNAs were obtained from the intersection of differentially expressed genes in different pathological types of TETs. Functional enrichment analysis showed that the DEmRNAs were closely related to cell proliferation and tumor development. After lncRNA-miRNA-mRNA network construction and external cohort validation, a total of 4 DEmRNAs DOCK11, MCAM, MYO10, and WASF3 were identified and their associated-ceRNA modules were significantly associated with prognosis, which contained 3 lncRNAs (lncRNA LINC00665, lncRNA NR2F1-AS1, and lncRNA RP11-285A1.1), 4 mRNAs (DOCK11, MCAM, MYO10, and WASF3), and 4 miRNAs (hsa-mir-143, hsa-mir-141, hsa-mir-140, and hsa-mir-3199). Meanwhile, ROC curves verified the accuracy of prediction ability of the screened ceRNA modules for prognosis of TETs. Conclusion: Our study revealed that ceRNAs modules might exert a crucial role in the progression of TETs. The mRNA associated-ceRNA modules could effectively predict the prognosis of TETs, which might be the potential prognostic and therapeutic markers for TETs patients.
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