Abstract
BackgroundN6-methyladenosine (m6A), the most abundant and reversible modification of mRNAs in eukaryotes, plays pivotal role in breast cancer (BC) tumorigenesis and progression. Circular RNAs (circRNAs) can act as tumor promoters or suppressors by microRNA (miRNA) sponges in BC. However, the underlying mechanism of circRNAs in BC progression via regulating m6A modulators remains unclear.MethodsPrognostic m6A RNA methylation regulators were identified in 1065 BC patients from The Cancer Genome Atlas (TCGA) project. Differentially expressed (DE) miRNAs and DE circRNAs were identified between BC and normal samples in TCGA and GSE101123, respectively. MiRNA-mRNA interactive pairs and circRNA-miRNA interactive pairs were verified by MiRDIP and Circular RNA Interactome. GSEA, KEGG, and ssGSEA were executed to explore the potential biological and immune functions between HNRNPC-high and HNRNPC-low expression groups. qRT-PCR and Western blot were used to quantify the expression of HNRNPC and circBACH2 in MCF-7 and MDA-MB-231 cells. The proliferation of BC cells was assessed by CCK-8 and EdU assay.Results2 m6A RNA methylation regulators with prognostic value, including HNRNPC and YTHDF3, were identified in BC patients. Then, the regulatory network of circRNA-miRNA-m6A modulators was constructed, which consisted of 2 DE m6A modulators (HNRNPC and YTHDF3), 12 DE miRNAs, and 11 DE circRNAs. Notably, BC patients with high expression of HNRNPC and low expression of hsa-miR-944 were correlated with late clinical stages and shorter survival times. Besides, the results from the KEGG inferred that the DE HNRNPC was associated with the MAPK signaling pathway in BC. Moreover, the circBACH2 (hsa_circ_0001625) was confirmed to act as hsa-miR-944 sponge to stimulate HNRNPC expression to promote BC cell proliferation via MAPK signaling pathway, thus constructing a circBACH2/hsa-miR-944/HNRNPC axis in BC.ConclusionsOur findings decipher a novel circRNA-based m6A regulatory mechanism involved in BC progression, thus providing attractive diagnostic and therapeutic strategies for combating BC.
Highlights
N6-methyladenosine (m6A), the most abundant and reversible modification of mRNAs in eukaryotes, plays pivotal role in breast cancer (BC) tumorigenesis and progression
Identification of Differentially expressed (DE) genes From previous studies, a total of 21 m6A methylation regulators were selected for identification [3, 13], and 17 m6A methylation regulators between 1065 BC patients and 112 normal samples were confirmed by Mann–Whitney-Wilcoxon Test according to the available mRNA expression data from The Cancer Genome Atlas (TCGA)
These results revealed that m6A regulatory genes exhibited differential expression patterns between BC and normal patients, which might provide a potential tool for BC diagnosis
Summary
N6-methyladenosine (m6A), the most abundant and reversible modification of mRNAs in eukaryotes, plays pivotal role in breast cancer (BC) tumorigenesis and progression. The underlying mechanism of circRNAs in BC progression via regulating m6A modulators remains unclear. The impacts of m6A on RNA are determined by the dynamic interactions between m6A RNA methylation modulators, including m6A methyltransferases (writers), binding proteins (readers), and demethylases (erasers) [3]. Emerging evidence indicates that m6A modifications are closely associated with tumorigenesis, tumor proliferation, differentiation, metastasis, and poor prognosis [8]. The writers, erasers, and readers of m6A RNA modification engage in the tumorigenesis and progression of BC. These BC-specific m6A modulators are potentially useful for serving as prognosis and therapy targets
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