MiR-24 induces chemotherapy resistance and hypoxic advantage in breast cancer.
MiR-24 induces chemotherapy resistance and hypoxic advantage in breast cancer.
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DOI：
10.18632/oncotarget.14470
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发表时间：
2017-03-21
期刊：
影响因子：
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通讯作者：
Condorelli G
中科院分区：
文献类型：
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作者：
Roscigno G;Puoti I;Giordano I;Donnarumma E;Russo V;Affinito A;Adamo A;Quintavalle C;Todaro M;Vivanco MD;Condorelli G
乳腺癌仍然是妇女癌症死亡的主要原因之一。已经证明，癌症的发生依赖于一个非常小的肿瘤细胞池，其表型与正常成体干细胞相似。肿瘤干细胞（CSC）具有自我更新和多向分化潜能，并具有强大的维持肿瘤发生的能力。有证据表明，CSC有助于化疗耐药性和缺氧条件下的生存。有趣的是，缺氧反过来又调节CSC的自我更新，这些作用可能主要由缺氧诱导因子（HIF）介导。最近，microRNAs（miRNAs）已成为维持正常和癌症干细胞多能性和自我更新的关键参与者。在这里，我们证明了miR-24在乳腺CSC中上调，并且其过表达增加了乳腺球的数量和干细胞标志物的表达。miR-24还通过调节BimL表达诱导凋亡抗性。此外，我们发现了一个新的miR-24靶点FIH 1，它可以促进HIFα的降解：miR-24在缺氧条件下增加，导致FIH 1下调和HIF 1 α上调。总之，miR-24通过FIH 1 −HIFα途径阻碍乳腺CSC中化疗诱导的凋亡，并增加细胞对缺氧条件的抵抗力。
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.