CircCRIM1 promotes ovarian cancer progression by working as ceRNAs of CRIM1 and targeting miR-383-5p/ZEB2 axis

Abstract

Background Ovarian cancer is the leading cause of death in patients with gynecologic cancer, and circular RNAs (circRNAs) are involved in cancer progression. However, there are limited studies on the roles of circRNAs in ovarian cancer. Methods We designed divergent and convergent primers, used sanger sequencing and RNase R digestion to verify the source of circCRIM1. We detected the expression of circCRIM1 and its parental gene cysteine rich transmembrane BMP regulator 1 (CRIM1) in ovarian cancer and normal ovarian samples via qRT-PCR. MTT viability assay, apoptosis assay, wound healing assay and invasion assay were used to investigate the function of circCRIM1 and CRIM1 in ovarian cancer cell lines OVCAR3 and CAOV3. Mice xenografts experiment was performed. Bioinformatics predicted the microRNAs that bond with circCRIM1 and CRIM1, and dual luciferase reporter system confirmed it. Rescue experiments of microRNAs mimics transfection on the basis of circCRIM1 over-expression were carried out to uncover the mechanism by which circCRIM1 played cancer-promoting roles in ovarian cancer. Results CircCRIM1 was derived from CRIM1 by back-splicing. CircCRIM1 and CRIM1 had higher expression in ovarian cancer than in normal ovarian tissues, and both of them promoted ovarian cancer progression in vitro. In vivo circCRIM1 promoted the growth of tumors. CircCRIM1 and CRIM1 had a positive correlation relationship in the same cohort of ovarian cancer tissues. Bioinformatics predicted and dual luciferase assay confirmed circCRIM1 and CRIM1 bond with miR-145-5p, and circCRIM1 bond with miR-383-5p additionally. CircCRIM1 positively affected the expression of CRIM1. After circCRIM1 was over-expressed, miR-145-5p mimics transfection reversed the expression of CRIM1. Western blot discovered circCRIM1 positively affected the expression of zinc finger E-box binding homeobox 2 (ZEB2). Rescue experiments found miR-383-5p mimics reversed ZEB2 expression and the cancer-promoting effects of circCRIM1. Conclusions CircCRIM1 bond with miR-145-5p to work as competing endogenous RNA (ceRNA) of CRIM1, and circCRIM1 bond with miR-383-5p to improve the expression of ZEB2 in ovarian cancer. CircCRIM1 and CRIM1 promoted the ovarian cancer progression and supplied a novel insight into the researches of ovarian cancer.

Hsa_circ_0000098 is a novel therapeutic target that promotes hepatocellular carcinoma development and resistance to doxorubicin

“…We further demonstrated that circ_0000098 regulated MCUR1 expression by competitive bonding with miR-383. According to previous reports, miR-383 is dysregulated in several cancers and controls their growth [ 28 , 29 ]. Long non-coding RNA CASC9-1 promotes cervical cancer progression by targeting miR-383 to upregulate MAPKAP1 [ 28 ].…”

“…Long non-coding RNA CASC9-1 promotes cervical cancer progression by targeting miR-383 to upregulate MAPKAP1 [ 28 ]. CircCRIM1 also promotes the tumorigenesis of ovarian cancer by targeting the miR-383/ZEB2 axis [ 29 ]. In our study, in vitro experiments supported that circ_0000098 increases HCC development through the miR-383/MCUR1 axis, however, the detailed impact of this signaling on HCC remains to be further investigated.…”

Pro-Inflammatory Cytokines Promote the Transcription of Circular RNAs in Human Pancreatic β Cells

“…circCRIM1 was implicated in promoting ovarian cancer progression by acting as a competitive endogenous RNA (ceRNA) for the host gene CRIM1 and targeting the miR-383-5p/ZEB2 axis [ 65 ]. CRIM1 encodes a transmembrane protein containing six cysteine-rich repeat domains and an insulin-like growth-factor-binding domain.…”

Circular RNAs in Epithelial Ovarian Cancer: From Biomarkers to Therapeutic Targets

“…CircCRIM1 harbors an ORF with 188 amino acids spanning the splice junction. Overexpression of this protein induced cell viability, migration and invasion, and inhibited apoptosis in EOC, suggesting a tumor-promoting activity of the circCRIM1-encoded protein [ 171 ]. However, whether circCRIM1 is endogenously translated into the protein remains to be confirmed.…”