Hypoxia-inducible factor-2α directly promotes BCRP expression and mediates the resistance of ovarian cancer stem cells to adriamycin
Hypoxia-inducible factor-2α directly promotes BCRP expression and mediates the resistance of ovarian cancer stem cells to adriamycin
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缺氧诱导因子2α直接促进BCRP表达并介导卵巢癌干细胞对阿霉素的耐药
DOI：
10.1002/1878-0261.12419
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发表时间：
2019-02-01
影响因子：
6.6
通讯作者：
Wei, Minjie
中科院分区：
文献类型：
--
作者：
He, Miao;Wu, Huizhe;Wei, Minjie
卵巢癌干细胞（OCSC）是肿瘤化疗耐药和复发的来源。低氧微环境有助于癌症干细胞（CSC）的化学抗性，但其潜在机制尚未完全了解。在这里，我们发现HIF-2 α表达的增加与卵巢癌患者中OCSC的干性增强和预后不良有关。OVCAR-3和CAOV-3球形成细胞（OVCAR-3S和CAOV-3S）具有OCSC样特性，对阿霉素（ADR）具有较强的抗性。缺氧（1%O-2）诱导HIF-1 α，尤其是HIF-2 α的高表达，并增加OVCAR-3S和CAOV-3S细胞对ADR的抵抗力。值得注意的是，ADR治疗进一步增加了HIF-2 α的表达，但没有增加HIF-1 α的表达。HIF-2 α表达的敲低显著减弱了OVCAR-3 S和CAOV-3 S细胞对ADR的耐药性，而HIF-2 α过表达则具有相反的效果。此外，在OCSC异种移植的小鼠模型中，HIF-2 α耗竭显著抑制肿瘤生长并使OCSC对体内ADR敏感。从机制上讲，HIF-2 α直接促进BCRP的转录/表达，BCRP是一种编码负责泵送药物的转运蛋白的基因（例如，ADR）从细胞中排出，这反过来又由于增加的药物转运而增加了耐药性。总的来说，我们的研究揭示了卵巢癌中一种新的耐药机制，即缺氧（和ADR治疗）诱导的HIF-2 α过表达通过促进BCRP表达和ADR转运赋予OCSC对ADR的抗性。因此，靶向HIF-2 α/BCRP轴具有治疗耐药卵巢癌的治疗潜力。
Ovarian cancer stem cells (OCSCs) are sources of tumor chemoresistance and recurrence. A hypoxic microenvironment contributes to the chemoresistance of cancer stem cells (CSCs), but the underlying mechanism is not fully understood yet. Here, we show that increased HIF-2 alpha expression is associated with enhanced stemness of OCSCs and poor outcomes in ovarian cancer patients. OVCAR-3 and CAOV-3 sphere-forming (OVCAR-3 S and CAOV-3 S) cells with OCSC-like properties showed strong resistance to adriamycin (ADR). Hypoxia (1% O-2) induced high expression of both HIF-1 alpha and especially HIF-2 alpha, and increased the resistance of OVCAR-3 S and CAOV-3 S cells to ADR. Notably, treatment with ADR further increased the expression of HIF-2 alpha, but not that of HIF-1 alpha. Knockdown of HIF-2 alpha expression substantially attenuated the resistance of OVCAR-3 S and CAOV-3 S cells to ADR, and the HIF-2 alpha overexpression had the opposite effect. Furthermore, in mouse models xenografted with OCSCs, HIF-2 alpha depletion significantly inhibited tumor growth and sensitized OCSCs to ADR in vivo. Mechanistically, HIF-2 alpha directly promotes transcription/expression of BCRP, a gene encoding a transporter protein responsible for pumping drugs (e.g., ADR) out of cells, which in turn increases drug resistance due to increased drug transportation. Collectively, our studies reveal a novel drug-resistant mechanism in ovarian cancer by which hypoxia (and ADR treatment)-induced HIF-2 alpha overexpression endows OCSCs with resistance to ADR by promoting BCRP expression and ADR transportation. Therefore, targeting the HIF-2 alpha/BCRP axis holds therapeutic potential for treating drug-resistant ovarian cancer.