Hsa_circ_0001947 suppresses acute myeloid leukemia progression by sponging hsa-miR-329-5p and regulating CREBRF expression

Abstract

13Acute myeloid leukemia (AML) is a heterogeneous group of diseases resulting 14 from clonal transformation of hematopoietic precursors through the acquisition of 15 chromosomal rearrangements and multiple gene mutations. Accumulating evidence 16 has indicated that aberrantly expressed circular RNAs (circRNAs) are involved in 17 cancer development and progression. However, their clinical values and biological 18 roles in AML remain unclear. In this study, we identified the aberrantly 19 down-regulated profile of hsa_circ_0001947 in AML through microarray analysis and 20 validated it with quantitative reverse transcription polymerase chain reaction 21 (qRT-PCR). Then, we explored the clinical significance, biological functions and 22 regulatory mechanisms of hsa_circ_0001947 in AML patients. The results showed 23 that lower hsa_circ_0001947 expression was positively correlated with higher 24 2 leukemia cells in bone marrow or peripheral blood, indicating poor prognosis. Further, 25 bioinformatics analysis demonstrated hsa_circ_0001947-hsa-miR-329-5p-CREBRF 26 network. Down-regulation of hsa_circ_0001947 by siRNA promoted cell proliferation, 27 inhibited apoptosis, reduced drug resistance of AML cells, and also decreased the 28 expression of its targeted gene, CREBRF. The mimics of hsa-miR-329-5p reduced 29 drug resistance and decreased the expression of CREBRF, while its inhibitor 30 manifested anti-leukemia effects and increased CREBRF expression. In vivo studies 31 revealed that silencing hsa_circ_0001947 promoted the tumor growth in BALB/c 32 nude mice. Collectively, our findings suggest that hsa_circ_0001947 functions as a 33 tumor inhibitor to suppress AML cell proliferation through hsa-miR-329-5p/CREBRF 34 axis, which would be a novel target for AML therapy. 35 CREBRF; therapy. 37 38 Recently it has been considered as the latest research hotspot in the field of RNAs[6]. 47 Unlike the traditional linear RNAs (containing 5'and 3' ends), circRNAs have a closed 48 continuous loops, which are difficult to be degraded by RNA exonuclease and are 49 3 more stable in expression [6-8]. The most common method of circRNAs biogenesis is 50 through backsplicing, in which the 5' splice site (5'ss) of a downstream exon is paired 51 with the 3'ss of an upstream exon[3]. Backsplicing can occur in both linear 52 pre-mRNAs and within lariat intermediates harboring skipped exons[9, 10]. 53 CircRNAs were reported to be cell-specific, which are relatively abundant in the brain 54 and exist in human body fluids such as blood[11]. The relationship between circRNAs 55 and linear RNA isoforms was complicated. There are reports that circRNAs are 56 produced in competition with linear RNAs[12]. However, it was also reported that 57 there is no definite correlation between circRNAs and liner RNAs[13]. CircRNAs 58 contain plenty of microRNA (miRNA) binding sites, which offer itself an important 59 role as the miRNAs sponge in cells. Through the function of binding certain miRNAs, 60 circRNA could eliminate the inhibitory effect of miR...

EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway

“…The above discovery compelled us to investigate the mechanisms underlying its silencing, which could aid in the development of effective Circ_0001187-activating agents. The biogenesis of circRNAs has been reported to be regulated both co and posttranscriptionally in cells (5,7). Both Circ_0001187 and DOPEY2 linear mRNA are derived from DOPEY2 pre-mRNA, and consistently, our results showed that DOPEY2 mRNA expression was positively correlated with Circ_0001187 expression (Figure 2J).…”

Long non-coding RNA NEAT1/miR-338-3p axis impedes the progression of acute myeloid leukemia via regulating CREBRF

“…Wong et al asserted that CREBRF was relevant to the regulation of high-density lipoproteinsinduced angiogenesis [37]. And Han et al announced that CREBRF worked as an inhibitory role in AML progression [19]. In accordance with this finding, CREBRF knockdown could reverse the inhibition of NEAT1 on AML progression, implying CREBRF was a repressor of AML.…”

“…CREB3 regulatory factor (CREBRF), a highly conserved protein, was reportedly acted as an anti-cancer gene of glioblastoma via obstructing the hypoxia-induced autophagy [18]. And CREBRF was shown to restrain the AML progression regulated by circRNA_0001947/miR-329-5p [19]. Nevertheless, it is unexplored whether CRE-BRF is a target for miR-338-3p and can be regulated by NEAT1 in AML.…”

Roles of circRNAs in hematological malignancies

“…Recent studies demonstrated the correlation between cir-cRNA expression and cell proliferation in hematological malignancies. For instance, circ-0004136 [60] promoted AML cell proliferation by sponging miR-142, while circ-0001947 [61] up-regulated CREBRF to repress AML cell proliferation by inhibiting hsa-miR-329-5p. In addition, circPOLA2 [62] and circ-0121582 [63] were overexpressed in AML and promoted cell proliferation by targeting their miRNAs.…”