The MS-lincRNA landscape reveals a novel lincRNA BCLIN25 that contributes to tumorigenesis by upregulating ERBB2 expression via epigenetic modification and RNA–RNA interactions in breast cancer

Abstract

AbstractThe landscape of molecular subtype-specific long intergenic noncoding RNAs (MS-lincRNAs) in breast cancer has not been elucidated. No study has investigated the biological function of BCLIN25, serving as a novel HER2 subtype-specific lincRNA, in human disease, especially in malignancy. Moreover, the mechanism of BCLIN25 in the regulation of ERBB2 expression remains unknown. Our present study aimed to investigate the role and underlying mechanism of BCLIN25 in the regulation of ERBB2 expression. The transcriptional landscape across five subtypes of breast cancer was investigated using RNA sequencing. Integrative transcriptomic analysis was performed to identify the landscape of novel lincRNAs. Next, WEKA was used to identify lincRNA-based subtype classification and MS-lincRNAs for breast cancer. The MS-lincRNAs were validated in 250 breast cancer samples in our cohort and datasets from The Cancer Genome Atlas and Gene Expression Omnibus. Furthermore, BCLIN25 was selected, and its role in tumorigenesis was examined in vitro and in vivo. Finally, the mechanism by which BCLIN25 regulates ERBB2 expression was investigated in detail. A total of 715 novel lincRNAs were differentially expressed across five breast cancer subtypes. Next, lincRNA-based subtype classifications and MS-lincRNAs were identified and validated using our breast cancer samples and public datasets. BCLIN25 was found to contribute to tumorigenesis in vitro and in vivo. Mechanistically, BCLIN25 was shown to increase the expression of ERBB2 by enhancing promoter CpG methylation of miR-125b, leading to miR-125b downregulation. In turn, ERBB2 mRNA degradation was found to be abolished due to decreased binding of miR-125b to the 3’-untranslated region (UTR) of ERBB2. These findings reveal the role of novel lincRNAs in breast cancer and provide a comprehensive landscape of breast cancer MS-lincRNAs, which may complement the current molecular classification system in breast cancer.