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1. Pharmacogenet Genomics. 2012 Mar;22(3):198-205.

MicroRNA profiling in K-562 cells under imatinib treatment: influence of miR-212
and miR-328 on ABCG2 expression.

Turrini E, Haenisch S, Laechelt S, Diewock T, Bruhn O, Cascorbi I.

aInstitute of Experimental and Clinical Pharmacology, University of Kiel, Kiel,
Germany bDepartment of Pharmacology, University of Bologna, Bologna, Italy.

BACKGROUND: Despite the enormous success of imatinib in chronic myeloid leukemia
(CML), therapy resistance has emerged in a significant proportion of patients,
partly because of the overexpression of ABC efflux transporters.
METHODS: Using an array comprising 667 miRNAs, we investigated whether the
expression of microRNAs (miRNAs) is altered in CML K-562 cells becoming resistant
to increasing concentrations of imatinib. ABCB1 and ABCG2 mRNA (quantitative
real-time PCR) and protein expression (western blot) were quantified under
short-term and 4 months' imatinib treatment. Interaction of miR-212 and miR-328
with ABCG2 was investigated by transfection experiments and reporter gene assays
using respective miRNA precursors or miRNA inhibitors.
RESULTS: Although ABCB1 protein was not expressed, ABCG2 protein was 7.2-fold
elevated after long-term treatment with 0.3 ┬Ámol/l imatinib and decreased
gradually at higher concentrations. miRNAs miR-212 and miR-328 were identified to
correlate inversely with ABCG2 expression under these conditions. Short-term
treatment also induced ABCG2 protein concentration dependently and caused a
downregulation of miR-212, but not of miR-328 at all tested concentrations
(P=0.050). Reporter gene assays confirmed miR-212 to target the 3'-UTR region of
ABCG2. In contrast, transfection of anti-miR-212 revealed an upregulation of
ABCG2 protein expression, whereas the effect of anti-miR-328 was weak.
CONCLUSION: Our study suggests an association of imatinib treatment, miRNA
downregulation and ABCG2 overexpression, possibly contributing to the mechanisms
involved in imatinib distribution and response in CML therapy.

PMID: 22241070 [PubMed - in process]