Extracellular ATP promotes breast cancer invasion and epithelial‐mesenchymal transition via hypoxia‐inducible factor 2α signaling
Extracellular ATP promotes breast cancer invasion and epithelial‐mesenchymal transition via hypoxia‐inducible factor 2α signaling
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细胞外 ATP 通过缺氧诱导因子 2α 信号促进乳腺癌侵袭和上皮间质转化
DOI：
10.1111/cas.14086
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发表时间：
2019-07
期刊：
影响因子：
5.7
通讯作者：
Weigang Fang
中科院分区：
文献类型：
--
作者：
Hui Yang;Yue-Hang Geng;Peng Wang;Yan-Ting Zhou;Han Yang;Yan-Fei Huo;Hongquan Zhang;Yan Li;Hui-ying He;Xin-Xia Tian;Weigang Fang
细胞外ATP已被证明在乳腺癌的侵袭和上皮间质转化（EMT）过程中发挥重要作用，但其机制尚不清楚。在此，我们通过使用cDNA微阵列，证明了细胞外ATP可以刺激缺氧诱导因子（HIF）信号传导，并上调缺氧诱导因子1/2α（HIF-1/2α）的表达。在用siRNA敲除HIF-1/2α后，我们发现HIF-2A-siRNA显著减弱了乳腺癌细胞中ATP驱动的侵袭和EMT。通过ChIP检测，我们发现细胞外ATP在侵袭和EMT过程中的生物学功能依赖于HIF-2α的直接靶点，其中赖氨酰氧化酶样2（LOXL 2）和基质金属蛋白酶-9（MMP-9）分别介导ATP驱动的侵袭，E-cadherin和Snail介导ATP驱动的EMT。此外，通过银染和质谱分析，我们发现磷酸甘油酸激酶1（PGK 1）可以与HIF-2α相互作用并介导ATP驱动的HIF-2α上调。此外，我们还证实了HIF-2α及其靶蛋白的表达可通过ATP介导的AKT-PGK 1途径进行调控。利用Balb/c小鼠肿瘤模型，阐明HIF-2α在体内促进肿瘤生长和转移中的作用。此外，通过搜索在线数据库，我们发现参与ATP-HIF-2α信号传导的分子在人乳腺癌组织中高表达，并且与不良预后相关。这些结果提示，细胞外ATP可通过HIF-2α信号通路促进乳腺癌的侵袭和EMT，这可能是未来抗转移治疗的潜在靶点。
Extracellular ATP has been shown to play an important role in invasion and the epithelial-mesenchymal transition (EMT) process in breast cancer; however, the mechanism is unclear. Here, by using a cDNA microarray, we demonstrated that extracellular ATP could stimulate hypoxia-inducible factor (HIF) signaling and upregulate hypoxia-inducible factor 1/2α (HIF-1/2α) expression. After knocking down HIF-1/2α using siRNA, we found that ATP-driven invasion and EMT were significantly attenuated via HIF2A-siRNA in breast cancer cells. By using ChIP assays, we revealed that the biological function of extracellular ATP in invasion and EMT process depended on HIF-2α direct targets, among which lysyl oxidase-like 2 (LOXL2) and matrix metalloproteinase-9 (MMP-9) mediated ATP-driven invasion, and E-cadherin and Snail mediated ATP-driven EMT, respectively. In addition, using silver staining and mass spectrometry, we found that phosphoglycerate kinase 1 (PGK1) could interact with HIF-2α and mediate ATP-driven HIF-2α upregulation. Furthermore, we demonstrated that expressions of HIF-2α and its target proteins could be regulated via ATP by AKT-PGK1 pathway. Using a Balb/c mice model, we illustrated the function of HIF-2α in promoting tumor growth and metastasis in vivo. Moreover, by exploring online databases, we found that molecules involved in ATP-HIF-2α signaling were highly expressed in human breast carcinoma tissues and were associated with poor prognosis. Altogether, these findings suggest that extracellular ATP could promote breast carcinoma invasion and EMT via HIF-2α signaling, which may be a potential target for future anti-metastasis therapy.
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影响因子：
5.7
作者：
Zhang JL;Liu Y;Yang H;Zhang HQ;Tian XX;Fang WG
通讯作者：
Fang WG
影响因子：
11.2
作者：
Salvador F;Martin A;López-Menéndez C;Moreno-Bueno G;Santos V;Vázquez-Naharro A;Santamaria PG;Morales S;Dubus PR;Muinelo-Romay L;López-López R;Tung JC;Weaver VM;Portillo F;Cano A
通讯作者：
Cano A
影响因子：
4
作者：
Oranuch Techatharatip;N. Nowwarote;S. Taebunpakul;P. Pavasant
通讯作者：
Oranuch Techatharatip;N. Nowwarote;S. Taebunpakul;P. Pavasant
DOI：
--
发表时间：
--
期刊：
--
影响因子：
--
作者：
Linda Holmquist-Mengelbier;E. Fredlund;Tobias Löfstedt;R. Noguera;S. Navarro;Helén Nilsson;A. Pietras;J. Vallon-Christersson;Å. Borg;K. Gradin;L. Poellinger;S. Påhlman
通讯作者：
Linda Holmquist-Mengelbier;E. Fredlund;Tobias Löfstedt;R. Noguera;S. Navarro;Helén Nilsson;A. Pietras;J. Vallon-Christersson;Å. Borg;K. Gradin;L. Poellinger;S. Påhlman
影响因子：
64.5
作者：
Manning BD;Toker A
通讯作者：
Toker A