CircRERE confers the resistance of multiple myeloma to bortezomib depending on the regulation of CD47 by exerting the sponge effect on miR-152-3p

Abstract

Background Inevitable resistance to chemotherapeutic drugs has become a major obstacle for the clinical treatment of multiple myeloma (MM). Circular RNAs (circRNAs) can regulate the chemoresistance in different tumors. Our study was to explore the regulation of circRNA arginine-glutamic acid dipeptide repeats (circRERE) in bortezomib (BTZ) resistance of MM. Methods CircRERE, microRNA-152-3p (miR-152-3p) and cluster of differentiation 47 (CD47) levels were assayed through the quantitative real-time polymerase chain reaction (qRT-PCR). Cell sensitivity to BTZ was analyzed using Cell Counting Kit-8 (CCK-8) assay. Cell proliferation and apoptosis were determined via colony formation assay and flow cytometry, respectively. The detection of all proteins was conducted by western blot. The target binding was analyzed via the dual-luciferase reporter assay and RIP assay. Results We found the upregulation of circRERE in BTZ-resistant MM samples and cells. BTZ resistance was inhibited after circRERE expression was downregulated in MM cells. CircRERE was identified to act as a miR-152-3p sponge. The effect of circRERE on the BTZ resistance was associated with the sponge function for miR-152-3p. CD47 was a target for miR-152-3p and circRERE could sponge miR-152-3p to generate the expression regulation of CD47. MiR-152-3p facilitated the susceptibility of MM cells to BTZ by targeting CD47. Conclusion These results suggested that circRERE could suppress the BTZ resistance in MM cells by mediating the miR-152-3p/CD47 axis.

The Role of NcRNAs to Regulate Immune Checkpoints in Cancer

“…CircRNA arginine–glutamic acid dipeptide repeat (circRERE) is a natural sponge of miR-152-3p, and the miR-152-3p inhibitor attenuated the suppressive effect of circRERE on bortezomib (BTZ) resistance ( 6 ). CD47 is associated with the degree of immune deactivation, and the therapeutic strategy concerning anti-CD47 has been employed to kill myeloma (MM) cells ( 110 , 111 ).…”

“…CD47 is associated with the degree of immune deactivation, and the therapeutic strategy concerning anti-CD47 has been employed to kill myeloma (MM) cells ( 110 , 111 ). In accordance with its sponge effects on miR-152-3p, circRERE modulates the resistance of BTZ in MM cells through suppressing miR-152-3p ( 6 ). Overexpression of miR-152-3p resulted in the repression of the IC 50 of BTZ and its cell proliferative ability, but accelerated cell apoptosis, which was then abolished by promotion of the expression of CD47.…”

“…Overexpression of miR-152-3p resulted in the repression of the IC 50 of BTZ and its cell proliferative ability, but accelerated cell apoptosis, which was then abolished by promotion of the expression of CD47. Protein detection by Western blot showed that, in 8226R5 and MM1, the upregulation of CD47 counteracted the miR-152-3p mimic-induced pro-apoptotic and anti-proliferative effects ( 6 ). BTZ is a first-line chemotherapeutic agent for MM, but treatment frequently fails due to the resistance to BTZ ( 112 ).…”

“…BTZ is a first-line chemotherapeutic agent for MM, but treatment frequently fails due to the resistance to BTZ ( 112 ). Moreover, CD47 is a downstream target of miR-152-3p, and miR-152-2p inhibits BTZ resistance by reducing the levels of CD47 in MM cells ( 6 ). Downregulation of circRERE may be a new therapeutic target by inducing BTZ resistance in MM treatment.…”

“…Some concrete miRNA systems are eminently related to the initiation and progression of cancer, as well as drug resistance ( 1 , 5 ). CircRNAs are covalently closed-loop ncRNAs without the 5′ and 3′ ends, and they are created by the back-splicing of pre-mRNAs ( 6 ). Additionally, they measure a category of ncRNAs or protein-coding RNAs derived from one coding DNA or multiple exons and are located within the living substance ( 7 , 8 ).…”