Coordinate up-regulation of hypoxia inducible factor (HIF)-1alpha and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing.
Coordinate up-regulation of hypoxia inducible factor (HIF)-1alpha and HIF-1 target genes during multi-stage epidermal carcinogenesis and wound healing.
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发表时间：
2000-11
期刊：
影响因子：
11.2
通讯作者：
D. Elson;H. Ryan;J. Snow;R. Johnson;J. Arbeit
中科院分区：
文献类型：
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作者：
D. Elson;H. Ryan;J. Snow;R. Johnson;J. Arbeit
癌发生和伤口愈合都经过增殖和组织重塑阶段。在这里，使用 K14-HPV16 转基因小鼠的多阶段表皮癌变模型或在非转基因小鼠中产生全层背部伤口，我们确定了缺氧诱导因子 (HIF)-1α 的表达模式，以及异二聚体转录因子 HIF-1、葡萄糖转运蛋白 (GLUT)-1、磷酸甘油酸激酶 (PGK)-1 和血管内皮生长因子 (VEGF) 的三个靶标。皮肤。在未受伤的非转基因皮肤中，HIF-1α、GLUT-1、PGK-1 和 VEGF mRNA 均未检测到。在表皮癌发生过程中，HIF-1α、GLUT-1、PGK-1和VEGF mRNA在早期增生中仅可检测到，在高度表皮胸部发育不良中显着增加，在浸润性鳞状癌中进一步增加。在肿瘤性皮肤中，HIF-1α、GLUT-1 和 PGK-1 mRNA 定位于基底和直接基底上表皮层，而 VEGF mRNA 主要表达于更上棘和颗粒表皮层。受伤后立即在伤口边缘的基底角质形成细胞中检测到 HIF-1α、GLUT-1 和 PGK-1 mRNA。所有三个基因的表达在上皮化基底角质形成细胞中均增加至最高水平，然后在伤口上皮化后降低至接近不可检测的水平。尽管VEGF mRNA在伤口愈合过程中也有类似的增加和减少，但其表达模式更加点状；在上皮化角质形成细胞的上棘层和颗粒层以及形态与巨噬细胞相似的真皮细胞中检测到最强烈的杂交信号。这些数据表明，在多阶段上皮癌发生和伤口愈合中，HIF-1α和HIF-1靶基因表达存在阶段特异性和时空控制。
Both carcinogenesis and wound healing proceed through stages of proliferation and tissue remodeling. Here, using either a model of multistage epidermal carcinogenesis in K14-HPV16 transgenic mice or creation of full-thickness back wounds in nontransgenic mice, we determined patterns of expression of hypoxia inducible factor (HIF)-1alpha, and three targets of the heterodimeric transcription factor HIF-1, glucose transporter (GLUT)-1, phosphoglycerate kinase (PGK)-1, and vascular endothelial growth factor (VEGF) in skin. Neither HIF-1alpha, GLUT-1, PGK-1, nor VEGF mRNA was detectable in unwounded nontransgenic skin. In epidermal carcinogenesis, HIF-1alpha, GLUT-1, PGK-1, and VEGF mRNAs were just detectable in early-stage hyperplasia, markedly increased in high-grade epidermal chest dysplasias, and further increased in invasive squamous carcinomas. In neoplastic skin, HIF-1alpha, GLUT-1, and PGK-1 mRNAs localized in the basal and immediate suprabasal epidermal layers, whereas VEGF mRNA was predominantly expressed in the more superior spinous and granular epidermal layers. Immediately after wounding, HIF-1alpha, GLUT-1, and PGK-1 mRNAs were detectable in basal keratinocytes at the wound edge. Expression of all three genes increased to maximum levels in reepithelializing basal keratinocytes and then diminished to near undetectable levels after wound epithelialization. Although VEGF mRNA similarly increased and decreased during wound healing, its expression pattern was more punctate; the most intense hybridization signals were detected in the upper spinous and granular layers of reepithelializing keratinocytes and in dermal cells morphologically similar to macrophages. These data suggest stage-specific and spatio-temporal control of HIF-1alpha and HIF-1 target gene expression in both multistage epithelial carcinogenesis and wound healing.