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Retinoic Acid Receptor ß Induces Terminal Differentiation of Squamous Cell Carcinoma Lines in the Absence of Cyclin-dependent Kinase Inhibitor Expression¹

Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, California 90033

The chemotherapeutic agent and vitamin A metabolite retinoic acid (RA) has been used to treat many tumor types. The effects of RA are mediated by a family of ligand-dependent transcription factors, the retinoic acid receptors (RAR) and the retinoid X receptors. Alterations in RAR expression have been implicated in tumorigenesis. We showed previously that loss of RARß expression and target gene responsiveness to RA were consistent features of head and neck squamous cell carcinoma lines. To begin to elucidate the role of RARß in the malignant transformation of stratified squamous epithelia, we reexpressed RARß in squamous cell carcinoma (SCC) lines by stable transfection. SCC lines expressing RARß produced large numbers of flat cells with abundant cytoplasm that died and detached from the culture dish. These cells morphologically resembled the differentiated cells of normal stratified squamous epithelium in culture. These cells did not exhibit the characteristic DNA fragmentation pattern of apoptotic cells, nor did they label in a fluorescent apoptosis assay. Northern and Western blotting revealed induction of terminal differentiation markers in these cells. RARß produced alterations in levels of RA-responsive gene expression in these cells, and terminal differentiation occurred in the absence of detectable cyclin-dependent kinase inhibitor expression. We concluded that RARß expression induced terminal differentiation in SCC lines, suggesting a role for this transcription factor in the normal maturation of stratified squamous epithelium.

¹ This study was supported by NIH Grant DE10966.

² To whom requests for reprints should be addressed, at Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033. Phone: (213) 342-3170; Fax: (213) 342-2981.

Received 5/23/97. Accepted 10/29/97.

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