Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates
Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates
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DOI：
10.1073/pnas.0402088101
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发表时间：
2004-05-25
影响因子：
11.1
通讯作者：
Kanangi, R
中科院分区：
文献类型：
--
作者：
Koike, T;Kimura, N;Kanangi, R
癌细胞经历不同的代谢变化来应对缺氧环境。这些变化至少部分是由称为缺氧诱导因子（hif）的转录因子的作用实现的。我们利用dna芯片技术和RT-PCR技术，研究了缺氧诱导培养的人结肠癌细胞的基因表达，特别是细胞粘附分子和具有细胞粘附活性的碳水化合物决定因子。低氧培养结肠癌细胞诱导选择素配体、细胞表面的sialyl Lewis x和sialyl Lewis a决定因子的表达显著增加，导致癌细胞对内皮细胞e -选择素的粘附明显增加。在肿瘤细胞中，低氧培养显著诱导了参与e -选择素碳水化合物配体合成的focusyltransferase VII （FUT7）、sialyltransferase st3gai （ST30）和udp -半乳糖转运蛋白-1 （UGT1）基因的转录。此外，syndecan-4 （SDC4）和alpha5-integrin （ITGA5）基因的转录也被显著诱导。细胞粘附分子参与癌细胞对纤维连接蛋白的增强粘附。缺氧对这些基因的转录诱导作用在荧光素酶报告基因试验中重现，这些基因被HIF的显性阴性形式共同转染显著抑制。这些结果表明，部分由hif介导的癌细胞的代谢变化通过选择素和整合素介导的途径显著增强了它们对血管内皮细胞的粘附，并表明这种增强进一步促进了癌症的血行转移和肿瘤血管生成。
Cancer cells undergo distinct metabolic changes to cope with their hypoxic environment. These changes are achieved at least partly by the action of transcriptional factors called hypoxia-inducible factors (HIFs). We investigated gene expression in cultured human colon cancer cells induced by hypoxic conditions with special reference to cell-adhesion molecules and carbohydrate determinants having cell-adhesive activity by using DNA-microarray and RT-PCR techniques. Hypoxic culture of colon cancer cells induced a marked increase in expression of selectin ligands, the sialyl Lewis x and sialyl Lewis a determinants at the cell surface, which led to a definite increase in cancer cell adhesion to endothelial E-selectin. The transcription of genes for fucosyltransferase VII (FUT7), sialyltransferase ST3GaI-I (ST30), and UDP-galactose transporter-1 (UGT1), which are all known to be involved in the synthesis of the carbohydrate ligands for E-selectin, was significantly induced in cancer cells by hypoxic culture in addition, a remarkable induction was detected in the genes for syndecan-4 (SDC4) and alpha5-integrin (ITGA5), the cell-adhesion molecules involved in the enhanced adhesion of cancer cells to fibronectin. The transcriptional induction by hypoxia was reproduced in the luciferase-reporter assays for these genes, which were significantly suppressed by the co-transfection of a dominant-negative form of HIF. These results indicate that the metabolic shifts of cancer cells partly mediated by HIFs significantly enhance their adhesion to vascular endothelial cells, through both selectin- and integrin-mediated pathways, and suggest that this enhancement further facilitates hematogenous metastasis of cancers and tumor angiogenesis.