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-HIFa pathway.

Roscigno G., Puoti I., Giordano I., Donnarumma E., Russo V., Affinito A., et al. (2017). MiR-24 induces chemotherapy resistance and hypoxic advantage in breast cancer. ONCOTARGET, 8(12), 19507-19521 [10.18632/oncotarget.14470].

MiR-24 induces chemotherapy resistance and hypoxic advantage in breast cancer

Todaro M.
Supervision
;
2017-01-01

Abstract

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-HIFa pathway.
Roscigno G., Puoti I., Giordano I., Donnarumma E., Russo V., Affinito A., et al. (2017). MiR-24 induces chemotherapy resistance and hypoxic advantage in breast cancer. ONCOTARGET, 8(12), 19507-19521 [10.18632/oncotarget.14470].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/416914
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