Ghrelin promotes oral tumor cell proliferation by modifying GLUT1 expression
Ghrelin promotes oral tumor cell proliferation by modifying GLUT1 expression
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DOI：
10.1007/s00018-015-2048-2
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发表时间：
2016-03-01
影响因子：
8
通讯作者：
Winter, Jochen
中科院分区：
文献类型：
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作者：
Kraus, Dominik;Reckenbeil, Jan;Winter, Jochen
在我们的研究中，研究了胃饥饿素对口腔肿瘤细胞的增殖作用和分子相关性。我们分析了胃饥饿素系统的所有分子组成部分，即胃饥饿素及其受体的存在，并利用实时荧光定量PCR和免疫组织化学技术进行检测。为了研究胃饥饿素对细胞的影响并阐明其下游调控机制，我们利用两种不同的口腔肿瘤细胞系（BHY和HN）进行细胞培养实验。用饥饿素刺激任一细胞系都能显著增加增殖。信号转导通过GSK-3 β的磷酸化和β -连环蛋白的核易位发生。这种作用可以通过阻断蛋白激酶a来抑制。葡萄糖转运蛋白1 （GLUT1）是向对这种碳水化合物有高需求的肿瘤细胞输送足量葡萄糖的重要因子（Warburg效应），外源性和内源性胃饥饿素上调了GLUT1的表达。使用siRNA沉默细胞内ghrelin浓度导致GLUT1表达和增殖显著降低。总之，我们的研究描述了食欲刺激肽激素ghrelin在葡萄糖摄取的特定方面在口腔癌增殖中的作用：(1)肿瘤细胞是ghrelin的来源。(2) Ghrelin通过自分泌和/或旁分泌活性影响肿瘤细胞增殖。(3) Ghrelin调节GLUT1的表达，间接促进肿瘤细胞增殖。这些发现具有重要的相关性，因为葡萄糖摄取被认为是癌症治疗的一个有希望的目标。
In our study, ghrelin was investigated with respect to its capacity on proliferative effects and molecular correlations on oral tumor cells. The presence of all molecular components of the ghrelin system, i.e., ghrelin and its receptors, was analyzed and could be detected using real-time PCR and immunohistochemistry. To examine cellular effects caused by ghrelin and to clarify downstream-regulatory mechanisms, two different oral tumor cell lines (BHY and HN) were used in cell culture experiments. Stimulation of either cell line with ghrelin led to a significantly increased proliferation. Signal transduction occurred through phosphorylation of GSK-3 beta and nuclear translocation of beta-catenin. This effect could be inhibited by blocking protein kinase A. Glucose transporter1 (GLUT1), as an important factor for delivering sufficient amounts of glucose to tumor cells having high requirements for this carbohydrate (Warburg effect) was up-regulated by exogenous and endogenous ghrelin. Silencing intracellular ghrelin concentrations using siRNA led to a significant decreased expression of GLUT1 and proliferation. In conclusion, our study describes the role for the appetite-stimulating peptide hormone ghrelin in oral cancer proliferation under the particular aspect of glucose uptake: (1) tumor cells are a source of ghrelin. (2) Ghrelin affects tumor cell proliferation through autocrine and/or paracrine activity. (3) Ghrelin modulates GLUT1 expression and thus indirectly enhances tumor cell proliferation. These findings are of major relevance, because glucose uptake is assumed to be a promising target for cancer treatment.