Identification of circRNA-miRNA-mRNA Networks to investigate lung adenocarcinoma pathogenesis based on whole-transcriptome analysis

Abstract Background The progression of lymph node metastasis has been elucidated in lung adenocarcinoma (LUAD), whist which and how transcripts worked in this process remains unclear. We aimed to investigate the markers and potential mechanism of lymph node metastasis in LUAD. Methods The whole-transcriptome sequencing was performed on the whole blood from the non-nodal metastasis (LUAD_low), lymph node metastasis (LUAD_high) lung adenocarcinoma patients and healthy people (Control). Subsequently, differential expression analysis among three groups was performed, followed by functional interaction prediction analysis to investigate gene-regulatory circuits in LUAD development. Then, following the rigorous selection, the competing endogenous RNAs (ceRNAs) networks mainly involved in ferroptosis were discovered, and a few of the miRNAs (such as hsa-miR-6509-3p, hsa-miR-6511a-3p, hsa-miR-6803-3p) and their central target gene ( IREB2 ) were validated in clinical specimens through qRT-PCR assays. Results Our results identified 75 differentially expressed messenger RNAs (dif-mRNAs), 125 differentially expressed microRNAs (dif-miRNAs), and 880 differentially expressed circular RNAs (dif-circRNAs) in non-nodal metastasis LUAD samples compared with Control; similarly, 352 dif-mRNAs, 3 dif-miRNAs, and 270 dif-circRNAs were found in advanced-stage LUAD compared with Control samples. Then the most comprehensive circRNA-associated ceRNA networks were constructed in the pathogenesis and metastasis of LUAD, respectively. Additionally, ferroptosis-associated miRNAs (such as hsa-miR-6509-3p, hsa-miR-6511a-3p, hsa-miR-6803-3p) were both significantly upregulated, whilst their central target gene ( IREB2 ) were obviously downregulated in LUAD tissues. Conclusion In summary, this study systematically demonstrated circRNA-associated ceRNA profiles in the development of LUAD, which could provide insights that facilitate LUAD diagnosis and therapy in the future.