MYC-Induced miR-203b-3p and miR-203a-3p Control Bcl-xL Expression and Paclitaxel Sensitivity in Tumor Cells

Sofia Aakko; Anne Hege Straume; Einar Elvbakken Birkeland; Ping Chen; Xi Qiao; Per Eystein' 'Lønning; Marko J Kallio

doi:10.1016/j.tranon.2018.10.001

MYC-Induced miR-203b-3p and miR-203a-3p Control Bcl-xL Expression and Paclitaxel Sensitivity in Tumor Cells

Transl Oncol. 2019 Jan;12(1):170-179. doi: 10.1016/j.tranon.2018.10.001. Epub 2018 Oct 22.

Authors

Sofia Aakko¹, Anne Hege Straume², Einar Elvbakken Birkeland², Ping Chen³, Xi Qiao⁴, Per Eystein' 'Lønning², Marko J Kallio⁵

Affiliations

¹ Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, 20520 Turku, Finland; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
² Department of Clinical Science, University of Bergen, 5020 Bergen, Norway; Department of Clinical Oncology, Haukeland University Hospital, 5020 Bergen, Norway.
³ Research Programs Unit, Genome-Scale Biology, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland; Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, SE-141 57, Huddinge, Sweden.
⁴ Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
⁵ Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, 20520 Turku, Finland; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland. Electronic address: marko.kallio@utu.fi.

Abstract

Taxanes are chemotherapeutic agents used in the treatment of solid tumors, particularly of breast, ovarian, and lung origin. However, patients show divergent therapy responses, and the molecular determinants of taxane sensitivity have remained elusive. Especially the signaling pathways that promote death of the taxane-treated cells are poorly characterized. Here we describe a novel part of a signaling route in which c-Myc enhances paclitaxel sensitivity through upregulation of miR-203b-3p and miR-203a-3p; two clustered antiapoptosis protein Bcl-xL controlling microRNAs. In vitro, the miR-203b-3p decreases the expression of Bcl-xL by direct targeting of the gene's mRNA 3'UTR. Notably, overexpression of the miR-203b-3p changed the fate of paclitaxel-treated breast and ovarian cancer cells from mitotic slippage to cell death. In breast tumors, high expression of the miR-203b-3p and MYC was associated with better therapy response and patient survival. Interestingly, in the breast tumors, MYC expression correlated negatively with BCL2L1 expression but positively with miR-203b-3p and miR-203a-3p. Finally, silencing of MYC suppressed the transcription of both miRNAs in breast tumor cells. Pending further validation, these results may assist in patient stratification for taxane therapy.