Chemotherapy is the preferred treatment for malignancies. However, a successful long-term use of chemotherapy is often prevented by the development of drug resistance. Many mechanisms such as gene mutation, DNA methylation and histone modification have important roles in the resistance of cancer cells to chemotherapeutic agents. Climent suggested miR-125b was involved in the development of drug resistance by microRNA (miRNA) dysregulation. miRNAs are endogenously expressed small non-coding RNAs, which are evolutionarily conserved and function as regulators of gene expression. Much effort has been exerted in analyzing the role of miRNAs in the development of drug resistance in a variety of malignancies. Several research groups have shown that the expressions of miRNAs in chemoresistant cancer cells and their parental chemosensitive ones are different. The molecular targets and mechanisms of chemosensitivity and chemoresistance are also elucidated. This article reviews the functions of miRNAs in the development of drug resistance.

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...