Abstract
BackgroundAlternative polyadenylation (APA) is a pervasive posttranscriptional mechanism regulating gene expression. However, the specific dysregulation of APA events and its potential biological or clinical significance in lung adenocarcinoma (LUAD) remain unclear.MethodsHere, we collected RNA-Seq data from two independent datasets: GSE40419 (n = 146) and The Cancer Genome Atlas (TCGA) LUAD (n = 542). The DaPars algorithm was employed to characterize the APA profiles in tumor and normal samples. Spearman correlation was used to assess the effects of APA regulators on 3′ UTR changes in tumors. The Cox proportional hazard model was used to identify clinically relevant APA events and regulators. We stratified 512 patients with LUAD in the TCGA cohort through consensus clustering based on the expression of APA factors.FindingsWe identified remarkably consistent alternative 3′ UTR isoforms between the two cohorts, most of which were shortened in LUAD. Our analyses further suggested that aberrant usage of proximal polyA sites resulted in escape from miRNA binding, thus increasing gene expression. Notably, we found that the 3′ UTR lengths of the mRNA transcriptome were correlated with the expression levels of APA factors. We further identified that CPSF2 and CPEB3 may serve as key regulators in both datasets. Finally, four LUAD subtypes according to different APA factor expression patterns displayed distinct clinical results and oncogenic features related to tumor microenvironment including immune, metabolic, and hypoxic status.InterpretationOur analyses characterize the APA profiles among patients with LUAD and identify two key regulators for APA events in LUAD, CPSF2 and CPEB3, which could serve as the potential prognostic genes in LUAD.
Highlights
MATERIALS AND METHODSNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide (Herbst et al, 2018)
The results indicated that oncogenes tended to have longer 3 untranslated regions (3 UTR) length than tumorsuppressor genes (TSGs) and other genes
The recurrent changed genes were highly enriched in the membrane (Figure 1F), suggesting that Alternative polyadenylation (APA) may be involved in regulating the localization of membrane proteins (Berkovits and Mayr, 2015) or the subcellular localization of mRNA transcripts for cancer-specific genes
Summary
MATERIALS AND METHODSNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide (Herbst et al, 2018). Advances in the characterization of alterations in the LUAD transcriptome facilitate interpretations of the complexity of the RNA processing-associated events, such as alternative splicing and polyadenylation, providing new perspectives on the oncogenic processes and signaling pathways in cancer development and progression (Esfahani et al, 2019). Alternative polyadenylation (APA) has been recognized as an important factor regulating gene expression. 70% of known human genes contain multiple polyA sites, which produce different lengths of 3 untranslated regions (3 UTR), thereby contributing to transcriptome diversity (Derti et al, 2012). Alternative polyadenylation (APA) is a pervasive posttranscriptional mechanism regulating gene expression. The specific dysregulation of APA events and its potential biological or clinical significance in lung adenocarcinoma (LUAD) remain unclear
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