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The Lysyl Oxidase LOX Is Absent in Basal and Squamous Cell Carcinomas and Its Knockdown Induces an Invading Phenotype in a Skin Equivalent Model

Authors' Affiliations: ¹ Laboratoire des Substituts Cutanés and ² Clinique dermatologique, Hôpital E. Herriot; ³ Institut de Biologie et de Chimie des Protéines, Centre National de la Recherche Scientifique, Université Lyon 1, Institut Fédératif de Recherches 128; and ⁴ Coletica, Lyon, France

Requests for reprints: Odile Damour, Laboratoire des Substituts Cutanés, Hôpital Edouard Herriot, Pavillon I, 5 place d'arsonval, 69437 Lyon Cedex 03, France. Phone: 33-4-7211-0618; Fax: 33-4-7211-0675; E-mail: odile.damour{at}chu-lyon.fr.

Lysyl oxidase initiates the enzymatic stage of collagen and elastin cross-linking. Among five isoforms comprising the lysyl oxidase family, LOX is the better studied. LOX is associated to an antitumor activity in ras-transformed fibroblasts, and its expression is down-regulated in many carcinomas. The aim of this work was to shed light on LOX functions within the epidermis by studying its expression in human basal and squamous cell carcinomas and analyzing the effect of its enzymatic activity inhibition and protein absence on human keratinocytes behavior in a skin equivalent. In both carcinomas, LOX expression by epidermal tumor cells was lacking, while it was up-regulated around invading tumor cells in association with the stromal reaction. Lysyl oxidase activity inhibition using ß-aminoproprionitrile in a skin equivalent model prepared with both primary human keratinocytes and HaCaT cell line affected keratin 10 and filaggrin expression and disorganized the collagen network and the basement membrane. In spite of all these changes, no invasion phenotype was observed. Modelization of the invasive phenotype was only noticed in the skin equivalent developed with LOX antisense HaCaT cell line, where the protein LOX is specifically absent. Our results clearly indicate that lysyl oxidase enzymatic activity is essential not only for the integrity maintenance of the dermis but also for the homeostasis of the epidermis. Moreover, LOX protein plays a role in the skin carcinomas and invasion but not through its enzymatic activity.

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