GLUT3 is induced during epithelial-mesenchymal transition and promotes tumor cell proliferation in non-small cell lung cancer.
GLUT3 is induced during epithelial-mesenchymal transition and promotes tumor cell proliferation in non-small cell lung cancer.
复制标题
DOI：
10.1186/2049-3002-2-11
复制
发表时间：
2014
影响因子：
5.9
通讯作者：
Meylan E
中科院分区：
文献类型：
--
作者：
Masin M;Vazquez J;Rossi S;Groeneveld S;Samson N;Schwalie PC;Deplancke B;Frawley LE;Gouttenoire J;Moradpour D;Oliver TG;Meylan E
糖代谢的改变和上皮-间质转化（EMT）是肿瘤向浸润性癌发展的两个重要特征。尽管对它们各自进行了广泛的表征，但EMT与肿瘤细胞葡萄糖代谢之间的联系仍然难以捉摸。在这里，我们表明，神经元葡萄糖转运蛋白GLUT 3有助于葡萄糖的摄取和增殖的肺肿瘤细胞已经经历了EMT。使用一组人非小细胞肺癌（NSCLC）细胞系，我们证明了GLUT 3在间充质细胞中强烈表达，而不是上皮细胞，这一发现在肝癌细胞中得到证实。此外，我们确定ZEB 1结合GLUT 3基因激活转录。重要的是，抑制GLUT 3表达减少了葡萄糖输入和间充质肺肿瘤细胞的增殖，而上皮细胞中的异位表达在低葡萄糖下维持增殖。使用人NSCLC的大的微阵列数据收集，我们确定GLUT 3表达与EMT标志物相关，并且是总体生存不良的预后。总之，我们的研究结果表明，GLUT 3是ZEB 1的转录靶点，这种葡萄糖转运蛋白在肺癌中起着重要作用，当肿瘤细胞失去其上皮特征变得更具侵袭性时。此外，这些发现强调了GLUT 3抑制药物作为治疗低分化肿瘤患者的靶向治疗的发展。
Alterations in glucose metabolism and epithelial-mesenchymal transition (EMT) constitute two important characteristics of carcinoma progression toward invasive cancer. Despite an extensive characterization of each of them separately, the links between EMT and glucose metabolism of tumor cells remain elusive. Here we show that the neuronal glucose transporter GLUT3 contributes to glucose uptake and proliferation of lung tumor cells that have undergone an EMT. Using a panel of human non-small cell lung cancer (NSCLC) cell lines, we demonstrate that GLUT3 is strongly expressed in mesenchymal, but not epithelial cells, a finding corroborated in hepatoma cells. Furthermore, we identify that ZEB1 binds to the GLUT3 gene to activate transcription. Importantly, inhibiting GLUT3 expression reduces glucose import and the proliferation of mesenchymal lung tumor cells, whereas ectopic expression in epithelial cells sustains proliferation in low glucose. Using a large microarray data collection of human NSCLCs, we determine that GLUT3 expression correlates with EMT markers and is prognostic of poor overall survival. Altogether, our results reveal that GLUT3 is a transcriptional target of ZEB1 and that this glucose transporter plays an important role in lung cancer, when tumor cells loose their epithelial characteristics to become more invasive. Moreover, these findings emphasize the development of GLUT3 inhibitory drugs as a targeted therapy for the treatment of patients with poorly differentiated tumors.