Studies on effect of hypoxia inducible factor on cell adhesion

细胞粘附分子参与各种疾病的病理生理学。不久前，我们一直在研究细胞粘附分子在恶性疾病中的功能意义。在研究过程中，我们注意到在缺氧条件下培养的细胞表现出很强的细胞粘附活性。对缺氧条件的反应涉及除癌症以外的多种疾病的病理生理学，例如糖尿病、肾病、动脉硬化、缺血性心脏病和器官移植。已知这些病症也与细胞粘附分子密切相关。在这个项目中，我们研究了缺氧条件下细胞粘附增强的机制。我们研究了基因表达在培养的人类细胞诱导的低氧条件下，特别是参考细胞粘附分子和碳水化合物的决定簇具有细胞粘附活性，使用DNA微阵列和RT-PCR技术。Hy ...更多信息 结肠癌细胞的培养物诱导选择素配体、细胞表面的唾液酸刘易斯x和唾液酸刘易斯a决定簇的表达显著增加，这导致癌细胞与内皮E-选择素的粘附的明确增加。FUT 7、ST 30和UGT 1的基因的转录，已知它们都参与E-选择素的碳水化合物配体的合成，在低氧培养的癌细胞中显著诱导。此外，在syndecan-4（SDC 4）和α5-整合素（ITGA 5）基因中检测到显著的诱导作用，这些细胞粘附分子参与癌细胞与纤连蛋白的粘附增强。在这些基因的荧光素酶报告基因检测中，缺氧引起的转录诱导被复制，这些基因被显性负性形式的HIF或转染显著抑制。这些结果表明，部分由HIF介导的癌细胞的代谢转变通过选择素和整合素介导的途径显著增强其与血管内皮细胞的粘附。少

Cell adhesion molecules are involved in the pathophysiology of various disorders. Some time ago, we had been engaged with the investigation of functional significance of cell adhesion molecules in malignant disorders. During the study, we had noticed that cells cultured under hypoxic conditions exhibit a strong cell adhesive activity. Response to hypoxic conditions is involved in the pathophysiology of wide variety of disorders other than cancers, such as diabetes, kidney diseases, arteriosclerosis, ischemic heart diseases and organ transplantation. These disorders are known to be closely related also to cell adhesion molecules. In this project we had investigated the mechanism involved in the enhancement of cell adhesion under hypoxic conditions. We investigated gene expression in cultured human cells induced by hypoxic conditions with special reference to cell adhesion molecules and carbohydrate determinants having cell adhesive activity using DNA microarray and RT-PCR techniques. Hy … More poxic 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, and this led to a definite increase in cancer cell adhesion to endothelial E-selectin The transcription of genes for FUT7,ST3O and 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 α5-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 ortransfection 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. Less