Unearthing Regulatory Axes of Breast Cancer circRNAs Networks to Find Novel Targets and Fathom Pivotal Mechanisms

Abstract

Circular RNAs (circRNAs) along other complementary regulatory elements in ceRNAs networks possess valuable characteristics for both diagnosis and treatment of several human cancers including breast cancer (BC). In this study, we combined several systems biology tools and approaches to identify influential BC circRNAs, RNA binding proteins (RBPs), miRNAs, and related mRNAs to study and decipher the BC triggering biological processes and pathways.Rooting from the identified total of 25 co-differentially expressed circRNAs (DECs) between triple negative (TN) and luminal A subtypes of BC from microarray analysis, five hub DECs (hsa_circ_0003227, hsa_circ_0001955, hsa_circ_0020080, hsa_circ_0001666, and hsa_circ_0065173) and top eleven RBPs (AGO1, AGO2, EIF4A3, FMRP, HuR (ELAVL1), IGF2BP1, IGF2BP2, IGF2BP3, EWSR1, FUS, and PTB) were explored to form the upper stream regulatory elements. All the hub circRNAs were regarded as super sponge having multiple miRNA response elements (MREs) for numerous miRNAs. Then four leading miRNAs (hsa-miR-149, hsa-miR-182, hsa-miR-383, and hsa-miR-873) accountable for BC progression were also introduced from merging several ceRNAs networks. The predicted 7-and 8-mer MREs matches between hub circRNAs and leading miRNAs ensured their enduring regulatory capability. The mined downstream mRNAs of the circRNAs-miRNAs network then were presented to STRING database to form the PPI network and deciphering the issue from another point of view. The BC interconnected enriched pathways and processes guarantee the merits of the ceRNAs networks' members as targetable therapeutic elements. This study suggested extensive panels of novel covering therapeutic targets that are in charge of BC progression in every aspect, hence their impressive role cannot be excluded and needs deeper empirical laboratory designs. Breast cancer (BC) is the most lethal cancer among women worldwide in 2017 [1]. To surpass the anti-cancer treatments' deficiencies, exploitation of all the novel high throughput data rooting from underlying microlayers of a disease is critical. Competing endogenous RNAs (ceRNAs) network which consists of various transcripts regulating each other at post-transcriptional level [2], is a complex and yet novel tracing means to investigate the breast cancer progression and metastasis. The interrelation between the transcripts that possess miRNA response elements (MREs), namely circular RNAs (circRNAs) and mRNAs is pivotal in the deciphering steps. The fundamental core of the ceRNA network is based on the ratio of affinity and competing for shared miRNAs MREs [3]. The circRNAs that were surmised to be non-coding, are now believed to be translated into proteins [4]. Apropos of being resistant to exonucleases and being more stable due to the lack of cap and poly A tales in their structure [5], possess myriad noteworthy functions in genes' expression regulations in cancer. They are divided into three subcategories regarding their source of emergence; exonic circRNA (ecRNA), exon-intron circRNA (ElciRNA)...

Circular RNA circ_SETD2 represses breast cancer progression via modulating the miR-155-5p/SCUBE2 axis

“…Moreover, circ_SETD2 introduction curbed tumor growth in vivo and repressed cell cycle progression, proliferation, migration, and invasion, and facilitated apoptosis of BC cells in vitro. Afzali et al discovered that circ_SETD2 was a differentially expressed gene that was downregulated in luminal A subtypes and triple-negative BC through microarray analysis [10]. Our data suggested that circ_SETD2 acted as a suppressor in BC, and the role of circ_SETD2 in BC was firstly reported.…”

“…Circular RNA circ_SETD2 (circ_SETD2), located at chr3:47155365-47168153 with a length of 4644 bp, is produced by reverse splicing of the SET domain containing 2 (SETD2) gene. circ_SETD2 was revealed to be a differentially expressed circRNA in luminal A subtypes and triple-negative BC [10]. However, the role of circ_SETD2 in BC and its related molecular mechanisms are indistinct.…”

hsa_circ_0001955 Enhances In Vitro Proliferation, Migration, and Invasion of HCC Cells through miR-145-5p/NRAS Axis

“…hsa_circ_0001955 has been reported to be differentially expressed between triple-negative and luminal A subtypes of breast cancer and may be involved in the carcinogenesis of breast cancer. 18 However, its function and mechanism in breast cancer and other human cancers, including HCC, have not been investigated. Consequently, we intended to ascertain whether hsa_circ_0001955 exerted oncogenic or tumor-suppressive roles in HCC.…”

Identification of the hsa_circ_0039466/miR-96-5p/FOXO1 regulatory network in hepatocellular carcinoma by whole-transcriptome analysis

“…After using differential expression analysis and retrieval of matched CSCD data, 8 cancer-specific circRNAs were selected for further research. A series of studies have verified that circRNAs, acting as miRNA sponges, promote the expression of downstream genes (29)(30)(31). Therefore, in our study, potential miRNA targets of the 8 circRNAs were predicted.…”