Identification of the Prognostic Enhancer RNA in Bladder Cancer Bone Metastasis

Background Bladder urothelial carcinoma (BLCA), one of the most common urinary system malignancies, has a high morbidity and metastasis rate. The enhancer RNAs (eRNAs), are derived from enhancer regions and contribute to enhancer function, whereas their roles in BLCA tumorigenesis and bone metastasis are still unclear.Method The RNA sequencing data of patients with BLCA were retrieved from The Cancer Genome Atlas (TCGA) databases and the normalized gene expression profile of eRNA in BLCA (annotated by Ensemble ID) were downloaded from the eRic database. The differential expression eRNAs and genes were evaluated and identified between primary BLCA with and without bone metastasis. The prognostic bone metastasis-specific eRNAs (PBMSEs) were screened by Lasso regression, and based on them, the risk scores were identified and predict models were constructed. Their accuracy were tested by the area under the curve (AUC) of the receiver operator characteristic (ROC) curve. Additionally, in order to explore the bone metastasis-specific regulation network, the relationship among key PBMSEs, differentially expressed target genes of eRNAs and signaling pathways were identified by Pearson correlation analysis. ResultsA total of 832 eRNAs were detected, with 37 PBMSEs annotated by Ensemble ID in univariate Cox regression analysis. Based on them, the first prediction model was constructed with the AUC of 0.920. Besides, we uncovered 166 DEGs between primary BLCA with and without bone metastasis. A total of 23 eRNAs and 109 target genes annotated by official gene symbol were uncovered in which31 PBMSEs and target genes revealed prognostic. Based on them, another prediction model was constructed with the AUC of 0.742. Moreover, we identified EMP1 as a PBMSE which regulated the target genes of APOLD1 and GPRC5A, and tumorigenesis-related pathways of KRAS signaling, inflammatory response, IL2-stat5 signaling and epithelial mesenchymal transition (EMT).Conclusion Our study identifies eRNAs as reliable indexes for prognosis and bone metastasis prediction in BLCA patients and provides well-applied prediction models for them. The bone metastasis-specific regulation network was also explored in which PBMSE (EMP1) could mediate target genes (APOLD1, GPRC5A) and tumorigenesis-related pathways (KRAS signaling, inflammatory response, EMT) in the tumorigenesis and bone metastasis of BLCA.