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

Cell surface receptors of the integral family regulate physiological and pathological processes in skin, including proliferation, differentiation, and malignant transformation. In skin, integrins are compartmentalized. While α6β4 is restricted to the basal surface of basal cells, β1 integrins are expressed in basal and suprabasal layers. In vivo and in Ca²⁺-induced differentiation of mouse keratinocytes in vitro, the loss of attachment to laminin via α6β4 integrin is an early event associated -with initiation of spinous differentiation. The restricted expression of α6β4 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 α6β4 suprabasally in an expanded proliferative compartment. The aberrant suprabasal α6β4 is associated with reduced keratin 1 expression and upregulation of keratin 13, keratin 8, and γ-glutamyltranspepti-dase. During malignant conversion, the increase in α6β4 protein and niRNA is associated with novel expression of an alternatively spliced form of the α6 subunit, α6B. The induction of α6B both in vivo and in vitro is particularly high in malignant cells produced by transduction of both v-fos and v-nw^Ha oncogenes into normal keratinocytes where it was associated with increased attachment to laminin. Furthermore, binding to laminin is increased by introduction of α6B into a papilloma cell line. These results establish a link between squamous tumor progression and the upregulation of the α6β4 integrin and suggest that expression of α6B could be functionally relevant to interaction of tumor cells with the laminin matrix during malignant conversion.