Inferring Cell Subtypes and LncRNA Function by a Cell-Specific CeRNA Network in Breast Cancer

Abstract

Single-cell RNA sequencing is a powerful tool to explore the heterogeneity of breast cancer. The identification of the cell subtype that responds to estrogen has profound significance in breast cancer research and treatment. The transcriptional regulation of estrogen is an intricate network involving crosstalk between protein-coding and non-coding RNAs, which is still largely unknown, particularly at the single cell level. Therefore, we proposed a novel strategy to specify cell subtypes based on a cell-specific ceRNA network (CCN). The CCN was constructed by integrating a cell-specific RNA-RNA co-expression network (RCN) with an existing ceRNA network. The cell-specific RCN was built based on single cell expression profiles with predefined reference cells. Heterogeneous cell subtypes were inferred by enriching RNAs in CCN to the estrogen response hallmark. Edge biomarkers were identified in the early estrogen response subtype. Topological analysis revealed that NEAT1 was a hub lncRNA for the early response subtype, and its ceRNAs could predict patient survival. Another hub lncRNA, DLEU2, could potentially be involved in GPCR signaling, based on CCN. The CCN method that we proposed here facilitates the inference of cell subtypes from a network perspective and explores the function of hub lncRNAs, which are promising targets for RNA-based therapeutics.

Tumor immune microenvironment lncRNAs

“…For the guilt-by-association approach, lncRNAs with expression levels that are highly correlated with that of PCGs are inferred to have a similar function, allowing one to predict lncRNA functions in silico ( Figure 1 A ). lncRNAs often directly interact with other RNA molecules, such as mRNAs originating from the sense strand or microRNAs (miRNAs), controlling the stability of sense mRNAs [ 45–48 ] or miRNA functions [ 49–55 ]. lncRNAs with abundant miRNA binding sites appear to function as ceRNAs that ‘sponge up’ miRNAs.…”