Elson D A, Ryan H E, Snow J W, Johnson R, Arbeit J M
Cutaneous Oncology Program, University of California-San Francisco Comprehensive Cancer Center, 94143-1674, USA.
Cancer Res. 2000 Nov 1;60(21):6189-95.
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.
致癌作用和伤口愈合均经历增殖和组织重塑阶段。在此，我们利用K14-HPV16转基因小鼠的多阶段表皮致癌模型或在非转基因小鼠背部制造全层伤口，确定了缺氧诱导因子（HIF）-1α以及异二聚体转录因子HIF-1的三个靶标——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）在皮肤中的表达模式。在未受伤的非转基因皮肤中，未检测到HIF-1α、GLUT-1、PGK-1或VEGF mRNA。在表皮致癌过程中，HIF-1α、GLUT-1、PGK-1和VEGF mRNA在早期增生阶段刚刚可检测到，在高级别表皮胸部发育异常中显著增加，在浸润性鳞状细胞癌中进一步增加。在肿瘤皮肤中，HIF-1α、GLUT-1和PGK-1 mRNA定位于基底和紧邻基底上层的表皮层，而VEGF mRNA主要在上层棘状和颗粒状表皮层表达。受伤后立即在伤口边缘的基底角质形成细胞中可检测到HIF-1α、GLUT-1和PGK-1 mRNA。这三个基因的表达在伤口再上皮化的基底角质形成细胞中增加到最高水平，然后在伤口上皮化后降至几乎不可检测的水平。虽然VEGF mRNA在伤口愈合过程中同样先增加后减少，但其表达模式更具点状；在再上皮化角质形成细胞的上层棘状和颗粒层以及形态上类似于巨噬细胞的真皮细胞中检测到最强的杂交信号。这些数据表明在多阶段上皮致癌作用和伤口愈合过程中，HIF-1α和HIF-1靶基因表达存在阶段特异性及时空控制。
