CircCD44 plays oncogenic roles in triple-negative breast cancer by modulating the miR-502\u20135p/KRAS and IGF2BP2/Myc axes

Jie Li,Ying Lin,Xinya Gao,Xunxun Lin,Nu Zhang,Xiaoli Liang,Zhanqiang Zhang,Maoguang Ma,Yuanhui Lai,Bo Lin,Weiming Lv,Xixi Li

doi:10.1186/s12943-021-01444-1

Abstract

BackgroundEmerging studies have revealed the potent functions of circRNAs in breast cancer tumorigenesis. However, the biogenesis, biofunction and mechanism of circRNAs in triple-negative breast cancer (TNBC) are largely unknown.MethodsHigh-throughput RNA sequencing was applied to identify dysregulated circRNAs in TNBCs and paired normal tissues. RNA pulldown and luciferase assays were performed to investigate the interaction between circular CD44 (circCD44, also annotated as hsa_circ_0021735) and miR-502–5p. RNA pulldown and RIP assays were used to investigate the interaction between circCD44 and IGF2BP2. Cell viability, colony formation, migration/invasion assays and in vivo tumorigenesis were used to investigate circCD44 biological functions.ResultsCircCD44 is an uncharacterized circRNA, which is highly expressed in TNBC, and its expression is negatively correlated with the prognosis of TNBC patients. CircCD44 promotes TNBC proliferation, migration, invasion and tumorigenesis at least partially by sponging miR-502–5p and interacting with IGF2BP2.ConclusionOur data suggested that overexpressed circCD44 promotes TNBC progression. CircCD44 is potentially a novel diagnostic and therapeutic marker for TNBC patients.

Highlights

Emerging studies have revealed the potent functions of Circular RNA (circRNA) in breast cancer tumorigenesis
CircCD44 was highly expressed in triple-negative breast cancer (TNBC), and its expression was negatively correlated with patient prognosis Five pairs of TNBCs and adjacent normal tissues were collected and subjected to circRNA sequencing as we previously described [13] (Fig. 1A)
Among the differentially expressed circRNAs, circCD44 was the most upregulated circRNA in TNBCs compared with normal tissues (Fig. 1B)

Summary

Introduction

Emerging studies have revealed the potent functions of circRNAs in breast cancer tumorigenesis. CircRNAs have been reported to be distributed widely across species and to play crucial roles, such as miRNA sponges, RNA binding proteins (RBPs) and protein coding templates, in tumorigenesis and cancer progression. Given their unique biological structure and vital functions, looking for circRNAs with high specificity and sensitivity will provide a new opportunity for the early diagnosis, clinical treatment, and prognosis monitoring of TNBC [10, 11]. CircSEPT9, induced by E2F1 and EIF4A3, promotes TNBC tumorigenesis and serves as a progression marker [12] Another circRNA, circHER2, encodes a polypeptide and resensitizes TNBC to pertuzumab-based treatment [13]. The roles of circRNAs in TNBC remain largely illusive

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Conclusion