Detection of novel biomarkers for early detection of Non-Muscle-Invasive Bladder Cancer using Competing Endogenous RNA network analysis

Bladder Cancer (BC) is one of the most common cancers in the world. Recent studies show that non-coding RNAs such as lncRNAs and circRNAs play critical roles in the progression of this cancer, but their regulatory relationships and functions are still largely unknown. As a new regulatory process within the cell, the coding and non-coding RNAs compete with each other to sponge their target miRNAs. This mechanism is described as “the competing endogenous RNA (ceRNA) hypothesis” which provides a new perspective to understand the regulation of gene expression in health and diseases such as cancer. In this study, to investigate the role of non-coding RNAs in BC, a new approach was used to reconstruct the ceRNA network for Non-Muscle Invasive Bladder Cancer (NMIBC) based on the expression data of coding and non-coding genes. Analysis of ceRNA networks in the early stage of BC led to the detection of an important module containing the lncRNA MEG3 as the central gene. The results show that the lncRNAs CARMN, FENDRR and ADAMTS9-AS2 may regulate MEG3 in NMIBC through sponging some important miRNAs such as miR-143-3p, miR-106a-5p and miR-34a-3p. Also, the lncRNA AC007608.2 is shown to be a potential BC related lncRNA for the first time based on ceRNA stage-specific network analysis. Furthermore, hub and altered genes in stage-specific and between stage networks led to the detection of hsa_circ_0017586 and hsa_circ_0001741 as novel potential circRNAs related to NMIBC. Finally, the hub genes in the networks were shown to be valuable candidates as biomarkers for the early stage diagnosis of BC.