Functional screen analysis reveals miR-3142 as central regulator in chemoresistance and proliferation through activation of the PTEN-AKT pathway in CML.

Chronic myeloid leukemia (CML) is caused by the constitutively active BCR-ABL tyrosine kinase. Although great progress has been made for improvement in clinical treatment during the past decades, it is common for patients to develop chemotherapy resistance. Therefore, further exploring novel therapeutic strategies are still crucial for improving disease outcome. MicroRNAs (miRNAs) represent a novel class of genes that function as negative regulators of gene expression. Recently, miRNAs have been implicated in several cancers. Previously, we identified 41 miRNAs that were dysregulated in resistant compared with adriamycin (ADR)-sensitive parental cells in CML. In the present study, we reported that miR-3142 are overexpressed in ADR-resistant K562/ADR cells and CML/multiple drug resistance patients, as compared with K562 cells and CML patients. Upregulation of miR-3142 in K562 cells accelerated colony formation ability and enhanced resisitance to ADR in vitro. Conversely, inhibition of miR-3142 expression in K562/ADR cells decreased colony-formation ability and enhanced sensitivity to ADR in vitro and in vivo. Significantly, our results showed miR-3142-induced ADR resistance through targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which led to downregulation of PTEN protein and activation of PI3 kinase (PI3K)/Akt pathway. Inhibition of Akt using Akt inhibitor or introduction of PTEN largely abrogated miR-3142-induced resistance. These findings indicated that miR-3142 induces cell proliferation and ADR resistance primarily through targeting the PTEN/PI3K/Akt pathway and implicate the potential application of miR-3142 in cancer therapy.