Amann Thomas, Maegdefrau Ulrike, Hartmann Arndt, Agaimy Abbas, Marienhagen Jörg, Weiss Thomas S, Stoeltzing Oliver, Warnecke Christina, Schölmerich Jürgen, Oefner Peter J, Kreutz Marina, Bosserhoff Anja K, Hellerbrand Claus
University of Regensburg, Department of Internal Medicine I, D-93042 Regensburg, Germany.
Am J Pathol. 2009 Apr;174(4):1544-52. doi: 10.2353/ajpath.2009.080596. Epub 2009 Mar 12.
Accelerated glycolysis is one of the biochemical characteristics of cancer cells. The glucose transporter isoform 1 (GLUT1) gene encodes a key rate-limiting factor in glucose transport into cancer cells. However, its expression level and functional significance in hepatocellular cancer (HCC) are still disputed. Therefore, we aimed to analyze the expression and function of the GLUT1 gene in cases of HCC. We found significantly higher GLUT1 mRNA expression levels in HCC tissues and cell lines compared with primary human hepatocytes and matched nontumor tissue. Immunohistochemical analysis of a tissue microarray of 152 HCC cases revealed a significant correlation between Glut1 protein expression levels and a higher Ki-67 labeling index, advanced tumor stages, and poor differentiation. Accordingly, suppression of GLUT1 expression by siRNA significantly impaired both the growth and migratory potential of HCC cells. Furthermore, inhibition of GLUT1 expression reduced both glucose uptake and lactate secretion. Hypoxic conditions further increased GLUT1 expression levels in HCC cells, and this induction was dependent on the activation of the transcription factor hypoxia-inducible factor-1alpha. In summary, our findings suggest that increased GLUT1 expression levels in HCC cells functionally affect tumorigenicity, and thus, we propose GLUT1 as an innovative therapeutic target for this highly aggressive tumor.
糖酵解加速是癌细胞的生化特征之一。葡萄糖转运蛋白异构体1（GLUT1）基因编码葡萄糖转运进入癌细胞过程中的关键限速因子。然而，其在肝细胞癌（HCC）中的表达水平及功能意义仍存在争议。因此，我们旨在分析GLUT1基因在HCC病例中的表达及功能。我们发现，与原代人肝细胞及配对的非肿瘤组织相比，HCC组织和细胞系中GLUT1 mRNA表达水平显著更高。对152例HCC病例的组织芯片进行免疫组化分析发现，Glut1蛋白表达水平与较高的Ki-67标记指数、肿瘤进展期及低分化显著相关。相应地，siRNA抑制GLUT1表达显著损害了HCC细胞的生长和迁移能力。此外，抑制GLUT1表达降低了葡萄糖摄取及乳酸分泌。低氧条件进一步增加了HCC细胞中GLUT1的表达水平，且这种诱导依赖于转录因子缺氧诱导因子-1α的激活。总之，我们的研究结果表明，HCC细胞中GLUT1表达水平升高在功能上影响肿瘤发生，因此，我们提出将GLUT1作为这种高侵袭性肿瘤的创新治疗靶点。
