MiR-24 induces chemotherapy resistance and hypoxic advantage in breast cancer
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Giuseppina Roscigno1,2,*, Ilaria Puoti1,2,*, Immacolata Giordano1, Elvira Donnarumma3, Valentina Russo1, Alessandra Affinito1, Assunta Adamo1, Cristina Quintavalle1,2, Matilde Todaro4, Maria dM Vivanco5, Gerolama Condorelli1,2
1Department of Molecular Medicine and Medical Biotechnology, “Federico II” University of Naples, Naples, Italy
2IEOS, CNR, Naples, Italy
3IRCCS-SDN, Naples, Italy
4Department of Pathobiology and Medical Biotechnology, University of Palermo, Palermo, Italy
5CIC bioGUNE, Centre for Cooperative Research in Biosciences, Derio, Spain
*These authors have contributed equally to the paper as first authors
Gerolama Condorelli, email: [email protected]
Keywords: microRNAs, breast cancer, cancer stem cells, BimL, FIH1
Received: May 17, 2016 Accepted: November 30, 2016 Published: January 03, 2017
Breast cancer remains one of the leading causes of cancer mortality among women. It has been proved that the onset of cancer depends on a very small pool of tumor cells with a phenotype similar to that of normal adult stem cells. Cancer stem cells (CSC) possess self-renewal and multilineage differentiation potential as well as a robust ability to sustain tumorigenesis. Evidence suggests that CSCs contribute to chemotherapy resistance and to survival under hypoxic conditions. Interestingly, hypoxia in turn regulates self-renewal in CSCs and these effects may be primarily mediated by hypoxic inducible factors (HIFs). Recently, microRNAs (miRNAs) have emerged as critical players in the maintenance of pluripotency and self-renewal in normal and cancer stem cells. Here, we demonstrate that miR-24 is upregulated in breast CSCs and that its overexpression increases the number of mammospheres and the expression of stem cell markers. MiR-24 also induces apoptosis resistance through the regulation of BimL expression. Moreover, we identify a new miR-24 target, FIH1, which promotes HIFα degradation: miR-24 increases under hypoxic conditions, causing downregulation of FIH1 and upregulation of HIF1α. In conclusion, miR-24 hampers chemotherapy-induced apoptosis in breast CSCs and increases cell resistance to hypoxic conditions through an FIH1−HIFα pathway.
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