Differential regulation of integrins and extracellular matrix binding in epidermal differentiation and squamous tumor progression

Abstract

Cell surface receptors of the integrin family regulate physiological and pathological processes in skin, including proliferation, differentiation, and malignant transformation. In skin, integrins are compartmentalized. While alpha 6 beta 4 is restricted to the basal surface of basal cells, beta 1 integrins are expressed in basal and suprabasal layers. In vivo and in Ca(2+)-induced differentiation of mouse keratinocytes in vitro, the loss of attachment to laminin via alpha 6 beta 4 integrin is an early event associated with initiation of spinous differentiation. The restricted expression of alpha 6 beta 4 to the basal cells in normal skin is disrupted early in the development of squamous cancer, where benign papillomas at high risk for malignant progression express alpha 6 beta 4 suprabasally in an expanded proliferative compartment. The aberrant suprabasal alpha 6 beta 4 is associated with reduced keratin 1 expression and upregulation of keratin 13, keratin 8, and gamma-glutamyltranspeptidase. During malignant conversion, the increase in alpha 6 beta 4 protein and mRNA is associated with novel expression of an alternatively spliced form of the alpha 6 subunit, alpha 6B. The induction of alpha 6B both in vivo and in vitro is particularly high in malignant cells produced by transduction of both v-fos and v-rasHa oncogenes into normal keratinocytes where it was associated with increased attachment to laminin. Furthermore, binding to laminin is increased by introduction of alpha 6B into a papilloma cell line. These results establish a link between squamous tumor progression and the upregulation of the alpha 6 beta 4 integrin and suggest that expression of alpha 6B could be functionally relevant to interaction of tumor cells with the laminin matrix during malignant conversion.