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Reactivation of Multiple Fetal miRNAs in Lung Adenocarcinoma.

ABSTRACT: MicroRNAs (miRNAs) play vital roles in the regulation of normal developmental pathways. However, cancer cells can co-opt these miRNAs, and the pathways that they regulate, to drive pro-tumourigenic phenotypes. Characterization of the miRNA transcriptomes of fetal organs is essential for identifying these oncofetal miRNAs, but it has been limited by fetal sample availability. As oncofetal miRNAs are absent from healthy adult lungs, they represent ideal targets for developing diagnostic and therapeutic strategies. We conducted small RNA sequencing of a rare collection of 25 human fetal lung (FL) samples and compared them to two independent cohorts (n = 140, n = 427), each comprised of adult non-neoplastic lung (ANL) and lung adenocarcinoma (LUAD) samples. We identified 13 oncofetal miRNAs that were expressed in FL and LUAD but not in ANL. These oncofetal miRNAs are potential biomarkers for LUAD detection (AUC = 0.963). Five of these miRNAs are derived from the imprinted C14MC miRNA cluster at the 14q32 locus, which has been associated with cancer development and abnormal fetal and placental development. Additionally, we observed the pulmonary expression of 44 previously unannotated miRNAs. The sequencing of these fetal lung samples also provides a baseline resource against which aberrant samples can be compared.

SUBMITTER: Cohn DE

PROVIDER: S-EPMC8199175 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLung adenocarcinoma (LUAD) is one of the most common cancers worldwide. The etiology and pathophysiology of LUAD remain unclear. The aim of the present study was to identify the key genes, miRNAs and transcription factors (TFs) associated with the pathogenesis and prognosis of LUAD.MethodsThree gene expression profiles (GSE43458, GSE32863, GSE74706) of LUAD were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by GEO2R.The Gene Ontology (GO) terms, pathways, and protein-protein interactions (PPIs) of these DEGs were analyzed. Bases on DEGs, the miRNAs and TFs were predicted. Furthermore, TF-gene-miRNA co-expression network was constructed to identify key genes, miRNAs and TFs by bioinformatic methods. The expressions and prognostic values of key genes, miRNAs and TFs were carried out through The Cancer Genome Atlas (TCGA) database and Kaplan Meier-plotter (KM) online dataset.ResultsA total of 337 overlapped DEGs (75 upregulated and 262 downregulated) of LUAD were identified from the three GSE datasets. Moreover, 851 miRNAs and 29 TFs were identified to be associated with these DEGs. In total, 10 hub genes, 10 key miRNAs and 10 key TFs were located in the central hub of the TF-gene-miRNA co-expression network, and validated using The Cancer Genome Atlas (TCGA) database. Specifically, seven genes (PHACTR2, MSRB3, GHR, PLSCR4, EPB41L2, NPNT, FBXO32), two miRNAs (hsa-let-7e-5p, hsa-miR-17-5p) and four TFs (STAT6, E2F1, ETS1, JUN) were identified to be associated with prognosis of LUAD, which have significantly different expressions between LUAD and normal lung tissue. Additionally, the miRNA/gene co-expression analysis also revealed that hsa-miR-17-5p and PLSCR4 have a significant negative co-expression relationship (r=?0.33, P=1.67e-14) in LUAD.ConclusionsOur study constructed a regulatory network of TF-gene-miRNA in LUAD, which may provide new insights about the interaction between genes, miRNAs and TFs in the pathogenesis of LUAD, and identify potential biomarkers or therapeutic targets for LUAD.

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Reactivation of Multiple Fetal miRNAs in Lung Adenocarcinoma.

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