FRE CNRS/URCA nο. 3481, Faculty of Pharmacy, 51096 Reims Cedex, France.
Int J Oncol. 2012 Jun;40(6):1797-804. doi: 10.3892/ijo.2012.1393. Epub 2012 Feb 29.
Collagen type I is an abundant component of the extracellular matrix and due to its longevity, constitutes a prominent target of non-enzymatic post-translational in vivo modifications such as carbamylation and glycation. These protein modifications involved in aging, renal diseases and diabetes, are linked to elevated cancer risk. In this in vitro study, we investigated the impact of carbamylated and glycated collagen type I on the migratory behavior of the highly invasive HT1080 human fibrosarcoma cells. The proliferation of HT1080 on modified collagens did not differ from that on native form. The glycated collagen delayed the cell adhesion time whereas the carbamylated one had no effect. The migration ability of HT1080 was studied by quantifying single cell speed using videomicroscopy. Glycation strongly inhibited mean cell speed by 47% whereas carbamylation moderately affected it by 12%. In addition, the influence of these collagen modifications on actin and vinculin organization was studied. On the glycated collagen, 63% of cells revealed a dramatic loss of actin stress fibers vs. 28% on the carbamylated one. In these cells, disorganized F-actin was accompanied with a disturbance of vinculin and both proteins were localized at the rim of the cells. Concerning the focal adhesion kinase (FAK) expression, glycated collagen only induced a significant inhibition. Whereas, both collagen modifications provoked a differential inhibition of FAK phosphorylation state by 25% for carbamylation and 60% for glycation. In conclusion, our data suggest that, in vivo, collagen glycation and carbamylation may affect tumor cell metastasis. This suggestion is supported by clinical studies reporting less aggressive tumors in diabetic or uremic patients. Consequently, the impact of such post-translational modifications has to be taken into account in order to better understand the link between aging, diabetes or uremia and cancer progression.
I 型胶原是细胞外基质的丰富成分，由于其寿命长，构成了非酶促体内翻译后修饰的突出靶点，如氨甲酰化和糖化。这些与衰老、肾脏疾病和糖尿病有关的蛋白质修饰与癌症风险升高有关。在这项体外研究中，我们研究了氨甲酰化和糖化 I 型胶原对高度侵袭性 HT1080 人纤维肉瘤细胞迁移行为的影响。HT1080 在改性胶原上的增殖与在天然形式上的增殖没有差异。糖化胶原延迟了细胞黏附时间，而氨甲酰化胶原则没有影响。通过使用视频显微镜量化单个细胞速度来研究 HT1080 的迁移能力。糖化强烈抑制了细胞平均速度 47%，而氨甲酰化则适度影响了细胞速度 12%。此外，还研究了这些胶原修饰对肌动蛋白和 vinculin 组织的影响。在糖化胶原上，63%的细胞显示出明显的肌动蛋白应力纤维丢失，而在氨甲酰化胶原上则为 28%。在这些细胞中，紊乱的 F-肌动蛋白伴随着 vinculin 的紊乱，这两种蛋白质都位于细胞的边缘。关于粘着斑激酶 (FAK) 的表达，糖化胶原仅诱导了显著的抑制。而两种胶原修饰均通过 25%的氨甲酰化和 60%的糖化导致 FAK 磷酸化状态的差异抑制。总之，我们的数据表明，在体内，胶原糖化和氨甲酰化可能影响肿瘤细胞转移。这一假设得到了临床研究的支持，这些研究报告糖尿病或尿毒症患者的肿瘤侵袭性较低。因此，必须考虑到这种翻译后修饰的影响，以便更好地理解衰老、糖尿病或尿毒症与癌症进展之间的联系。
