title: 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.
authors.affiliation: Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute National Institutes of Health, bethesda, Maryland 20892-4355, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tennenbaum
authors.forename: A J
authors.initials: AJ
authors.lastname: Belanger
authors.forename: V
authors.initials: V
authors.lastname: Quaranta
authors.forename: S H
authors.initials: SH
authors.lastname: Yuspa
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D002454:Cell Differentiation; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D006801:Humans; D039161:Integrin alpha6beta4; D016023:Integrins / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism*; D051379:Mice; D012878:Skin Neoplasms / Q000209:etiology*
chemical_list: D000954:Antigens, Surface; D039161:Integrin alpha6beta4; D016023:Integrins; D007797:Laminin