Upregulation of miR-181c inhibits chemoresistance by targeting ST8SIA4 in chronic myelocytic leukemia

Published version. Source at http://doi.org/10.18632/oncotarget.11054. License CC BY 3.0. Chemotherapy resistance frequently drives tumor progression. Increased expression of ST8SIA4 has been reported in diverse carcinomas and highly correlates with leukemia multidrug resistance (MDR). MicroRNAs (miRNA) are widely recognized as key players in cancer progression and drug resistance. Here, to explore whether miRNA modulates the sensitivity of chronic myelocytic leukemia (CML) to chemotherapeutic agents and regulates ST8SIA4 expression, we analyzed the complete miRNA expression profile and found a subset of miRNAs specifically dysregulated in adriamycin-resistant CML cell line K562/ADR and its parent cell line K562. Compared with three pairs of CML cell lines and 38 clinical samples of peripheral blood mononuclear cells (PBMC) of CML patients, miR-181c expression was down-regulated in drug-resistant cell lines and CML/MDR samples. Altered expression levels of miR-181c influenced the MDR phenotypes of K562 and K562/ADR. Reporter-gene assay showed that miR-181c directly targeted and inhibited the ST8SIA4 expression, as well as miR-181c was inversely correlated with the levels of ST8SIA4 expression in CML cell lines and samples. Moreover, ST8SIA4 could reverse the effect of miR-181c on drug resistance in K562 and K562/ADR cells in vitro. Upregulation of miR-181c sensitized K562/ADR cells to adriamycin in vivo through directly suppressing ST8SIA4 expression. Further investigation showed that miR-181c mediated the activity of phosphoinositide-3 kinase (PI3K)/AKT signal pathway, and inhibition of PI3K/Akt in K562 cells counteracted miR-181c-mediated MDR phenotype. These data revealed an important role for miR-181c in the regulation of chemoresistance in CML, and suggested the potential application of miR-181c in drug resistance treatment.