HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways.
HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways.
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HIF-2 通过激活 Wnt 和 Notch 通路促进向干细胞表型的转化并诱导乳腺癌细胞的化疗耐药性
DOI：
10.1186/s13046-018-0925-x
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发表时间：
2018-10-19
期刊：
影响因子：
--
通讯作者：
Wei M
中科院分区：
文献类型：
--
作者：
Yan Y;Liu F;Han L;Zhao L;Chen J;Olopade OI;He M;Wei M
乳腺癌耐药的原因是肿瘤微环境的低下和干细胞的维持。然而，缺氧诱导因子-2 α（HIF-2α）在缺氧肿瘤微环境中是否介导乳腺肿瘤向干细胞表型的转化和化疗耐药性尚未阐明。采用qRT-PCR和western blot检测HIF-1α、HIF-2α、Wnt和Notch通路的mRNA和蛋白表达。MTT法、流式细胞仪和软琼脂集落形成法检测细胞活力和更新能力。在我们的研究中，急性缺氧（6-12 h）短暂增加HIF-1α的表达，而慢性缺氧（48 h）持续增加HIF-2α的表达，并诱导乳腺癌细胞对紫杉醇（PTX）的抵抗。此外，HIF-2α过表达诱导干细胞表型、对PTX的抗性以及干细胞标志物c-Myc、OCT 4和Nanog的蛋白表达增强。最重要的是，Wnt和Notch信号通路（不包括Shh）都被HIF-2α过表达激活。Wnt通路抑制剂Dickkopf-1（DKK-1）和Notch通路抑制剂L 685，458逆转了HIF-2α过表达诱导的PTX抗性和干细胞表型转换。此外，HIF-2α过表达增强了异种移植肿瘤的致瘤性和对紫杉醇的耐药性，增加了Wnt和Notch途径的激活，并在体内诱导了干细胞表型。总之，HIF-2α通过激活Wnt和Notch途径促进茎表型转化并诱导对PTX的抗性。本文的在线版本（10.1186/s13046-018-0925-x）包含补充材料，可供授权用户使用。
Hypoxic tumor microenvironment and maintenance of stemness contribute to drug resistance in breast cancer. However, whether Hypoxia-inducible factor-2α (HIF-2α) in hypoxic tumor microenvironment mediates conversion to a stem cell phenotype and chemoresistance of breast tumors has not been elucidated. The mRNA and protein expressions of HIF-1α, HIF-2α, Wnt and Notch pathway were determined using qRT-PCR and western blot. Cell viability and renew ability were assessed by MTT, Flow cytometric analysis and soft agar colony formation. In our study, acute hypoxia (6–12 h) briefly increased HIF-1α expression, while chronic hypoxia (48 h) continuously enhanced HIF-2α expression and induced the resistance of breast cancer cells to Paclitaxel (PTX). Furthermore, HIF-2α overexpression induced a stem cell phenotype, the resistance to PTX and enhanced protein expression of stem cell markers, c-Myc, OCT4 and Nanog. Most importantly, Wnt and Notch signaling, but not including Shh, pathways were both activated by HIF-2α overexpression. Dickkopf-1 (DKK-1), a Wnt pathway inhibitor, and L685,458, an inhibitor of the Notch pathway, reversed the resistance to PTX and stem phenotype conversion induced by HIF-2α overexpression. In addition, HIF-2α overexpression enhanced tumorigenicity and resistance of xenograft tumors to PTX, increased activation of the Wnt and Notch pathways and induced a stem cell phenotype in vivo. In conclusion, HIF-2α promoted stem phenotype conversion and induced resistance to PTX by activating Wnt and Notch pathways. The online version of this article (10.1186/s13046-018-0925-x) contains supplementary material, which is available to authorized users.
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DOI：
10.4161/cc.8.20.9701
发表时间：
2009-10-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Heddleston JM;Li Z;McLendon RE;Hjelmeland AB;Rich JN
通讯作者：
Rich JN
影响因子：
--
作者：
Bayin NS;Frenster JD;Sen R;Si S;Modrek AS;Galifianakis N;Dolgalev I;Ortenzi V;Illa-Bochaca I;Khahera A;Serrano J;Chiriboga L;Zagzag D;Golfinos JG;Doyle W;Tsirigos A;Heguy A;Chesler M;Barcellos-Hoff MH;Snuderl M;Placantonakis DG
通讯作者：
Placantonakis DG
影响因子：
5.5
作者：
Fallah Y;Brundage J;Allegakoen P;Shajahan-Haq AN
通讯作者：
Shajahan-Haq AN
影响因子：
--
作者：
Alam MW;Persson CU;Reinbothe S;Kazi JU;Rönnstrand L;Wigerup C;Ditzel HJ;Lykkesfeldt AE;Påhlman S;Jögi A
通讯作者：
Jögi A
影响因子：
11.2
作者：
Pannequin, Julie;Bonnans, Caroline;Hollande, Frederic
通讯作者：
Hollande, Frederic