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Abnormal Expression of Retinoic Acid Receptors and Keratin 19 by Human Oral and Epidermal Squamous Cell Carcinoma Cell Lines¹

Departments of Biological Chemistry and Molecular Pharmacology [L. H., L. J. G.] and Cellular and Molecular Physiology [J. G. R.], Harvard Medical School, and the Divisions of Cellular and Molecular Biology [L. H., L. J. G.] and Cell Growth and Regulation [D. L. C., J. G. R.], Dana-Farber Cancer Institute, Boston, Massachusetts 02115; the Department of Oral Medicine and Oral Pathology, Harvard School of Dental Medicine, Boston, Massachusetts 02115 [D. L. C.]; and the Laboratoire de Génétique Moléculaire des Eucaryotes du Centre National de la Recherche Scientifique, Unite 184 de Biologie Moléculaire et de Génie Génétique de l'Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine, 11, rue Humann, 67085 Strasbourg Cedex, France [P. C.]

We have analyzed the expression of the three retinoic acid receptor (RAR) (, ß, ) mRNAs and the intermediate filament protein keratin 19 (K19) mRNA in cell lines cultured from oral and epidermal human squamous cell carcinoma (SCC) and from benign, hyperplastic, and hyperkeratotic (leukoplakia) lesions arising in various regions of the oral cavity. Seven of the SCC lines were derived from tumors arising in regions of the oral cavity in which the normal epithelial cells (keratinocytes) express RARß transcripts. Seven of the nine SCC lines tested did not exhibit detectable RARß mRNA levels, even in response to addition or deleted in the five nonexpressing SCC lines examined by Southern analysis. The steady-state RAR mRNA levels were 2- to 4-fold lower in 6 of the 9 SCC lines than in their normal counterparts, whereas the RAR message levels in SCC lines were similar to those of the normal cell strains. The expression of keratin 19 message, which is RA inducible in normal keratinocytes, was also abnormal in many of the SCC cell lines. Some SCC lines, e.g., those derived from tumors of the soft palate epithelium, did not express high levels of K19 message even though normal soft palate keratinocytes expressed high levels of K19 mRNA. Two of the nine SCC lines expressed higher than normal levels of K19 mRNA, and this expression was RA independent. Cells cultured from four oral leukoplakia lesions were also examined and found to express RARß mRNA at relatively normal levels, but they expressed RAR message at half the level of epithelial cells cultured from normal tissue. These results show that the correlation between RARß gene expression and K19 gene expression that we have observed in the various normal keratinocyte subtypes of the oral cavity (D. L. Crowe et al., manuscript in preparation) is not present in transformed keratinocytes (SCC cells). The lack of apparent RA regulation of the K19 gene in SCC lines may be associated with other aberrations in differentiation which have been identified in SCC cells. Abnormally low expression of the RARß receptor may contribute to neoplastic progression in stratified squamous epithelia. It may also determine whether a tumor is responsive to RA as a chemotherapeutic agent.

¹ This work was supported by NIH Grant R01CA26656 and a grant from the National Foundation for Cancer Research to J. G. R. and American Cancer Society Grant CN41 to L. J. G. L. H. is a Fellow of the Leukemia Society of America. D. L. C. is supported by NIH Training Grant DE07117-09.

² Present address: Department of Research and Development, BioSurface Technology, Inc., 64 Sidney Street, Cambridge, MA 02139.

³ To whom requests for reprints should be addressed, at Department of Pharmacology, Cornell University Medical College, 1300 York Avenue, New York, NY 10021.

Received 3/20/91. Accepted 5/23/91.

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