RNA-binding protein IGF2BP2 enhances circ_0000745 abundancy and promotes aggressiveness and stemness of ovarian cancer cells via the microRNA-3187-3p/ERBB4/PI3K/AKT axis

Shengtan Wang,Chunyan Hu,Lan Hong,Kang Wang,Chunbo Hao,Kaiying Cui,Genhai Zhu,Zaihong Li

doi:10.1186/s13048-021-00917-7

Shengtan Wang, Chunyan Hu + Show 6 more

Open Access

https://doi.org/10.1186/s13048-021-00917-7

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Abstract

BackgroundCircular RNAs (circRNAs) are increasingly recognized as important regulators in cancer including ovarian cancer (OC). This work focuses on the effects of circ_0000745 on the OC development of and molecules involved.MethodsExpression of circ_0000745 in collected OC tissues and the acquired OC cell lines was examined by RT-qPCR. The stability of circ_0000745 in cells was examined by RNase R treatment. The target transcripts interacted with circ_0000745 were predicted using bioinformatic systems. Gain- and loss-of-function studies of circ_0000745, microRNA (miR)-3187-3p and erb-b2 receptor tyrosine kinase 4 (ERBB4) were conducted to determine their functions on proliferation, migration, invasion and stem cell property of OC cells.ResultsCirc_0000745 and ERBB4 were abundantly expressed while miR-3187-3p was poorly expressed in OC tissues and cells. Circ_0000745 sequestered miR-3187-3p and blocked its repressive effect on ERBB4. Downregulation of circ_0000745 reduced proliferation, aggressiveness, epithelial-mesenchymal transition, and stemness of SK-OV-3 cells, but this reduction was blocked upon miR-3187-3p inhibition or ERBB4 upregulation. By contrast, artificial induction of circ_0000745 upregulation, miR-3187-3p upregulation and ERBB4 downregulation led to inverse trends in ES-2 cells. ERBB4 promoted the phosphorylation of the PI3K/AKT signaling pathway. An RNA binding protein IGF2BP2 was found to circ_0000745 bind to and promote its expression and stability.ConclusionThis study demonstrated that circ_0000745 upregulated by IGF2BP2 promotes aggressiveness and stemness of OC cells through a miR-3187-3p/ERBB4/PI3K/AKT axis. Circ_0000745 may serve as a promising target for OC treatment.

Highlights

Ovarian cancer (OC) represents one of the most frequent and life-threatening gynecologic tumors with high morbidity and mortality rates across the globe, with 295,414 new cases and 184,799 deaths reported in 2018 [1]
It was found that the circ_0000745 expression was increased in ovarian cancer (OC) tumor tissues compared to the adjacent tissues (Fig. 1B)
Similar trends were found by the colony formation assay where we found increased colonies formed by ES-2 cells while decreased colonies formed by SK-OV-3 cells (Fig. 2C)

Summary

Introduction

Ovarian cancer (OC) represents one of the most frequent and life-threatening gynecologic tumors with high morbidity and mortality rates across the globe, with 295,414 new cases and 184,799 deaths reported in 2018 [1]. Circular RNAs (circRNAs) represent a major class of non-coding RNAs (ncRNAs) in animals in closed loop structure with potent regulatory ability and high stability [5]. These ubiquitous, stable, and conserved RNA molecules with an array of activities including translation and splicing regulation, are capable of interacting with RNA binding proteins (RBPs) and microRNA (miRNA) [6]. Poor expression of miR-3187-3p has been reported to be associated with reduced recurrence-free survival rate in patients with bladder cancer [9]. This work focuses on the effects of circ_0000745 on the OC development of and molecules involved

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Conclusion