title: Changes in the expression of miR-381 and miR-495 are inversely associated with the expression of the MDR1 gene and development of multi-drug resistance.
abstract: Multidrug resistance (MDR) frequently develops in cancer patients exposed to chemotherapeutic agents and is usually brought about by over-expression of P-glycoprotein (P-gp) which acts as a drug efflux pump to reduce the intracellular concentration of the drug(s). Thus, inhibiting P-gp expression might assist in overcoming MDR in cancer chemotherapy. MiRNAome profiling using next-generation sequencing identified differentially expressed microRNAs (miRs) between parental K562 cells and MDR K562 cells (K562/ADM) induced by adriamycin treatment. Two miRs, miR-381 and miR-495, that were strongly down-regulated in K562/ADM cells, are validated to target the 3'-UTR of the MDR1 gene. These miRs are located within a miR cluster located at chromosome region 14q32.31, and all miRs in this cluster appear to be down-regulated in K562/ADM cells. Functional analysis indicated that restoring expression of miR-381 or miR-495 in K562/ADM cells was correlated with reduced expression of the MDR1 gene and its protein product, P-gp, and increased drug uptake by the cells. Thus, we have demonstrated that changing the levels of certain miR species modulates the MDR phenotype in leukemia cells, and propose further exploration of the use of miR-based therapies to overcome MDR.
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China ; Department of Genome Biology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia ; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ohms
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wang
authors.forename: Guangming
authors.initials: G
authors.lastname: Gong
authors.forename: Yiqiao
authors.initials: Y
authors.lastname: Hu
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Mao
authors.forename: M Frances
authors.initials: MF
authors.lastname: Shannon
authors.forename: Jun Y
authors.initials: JY
authors.lastname: Fan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D020029:Base Pairing; D001483:Base Sequence; D045744:Cell Line, Tumor; D002883:Chromosomes, Human, Pair 14; D018432:Drug Resistance, Multiple / Q000235:genetics*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D005810:Multigene Family; D015203:Reproducibility of Results
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C588249:MIRN381 microRNA, human; C577768:MIRN495 microRNA, human; D035683:MicroRNAs