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Diminished Expression of C/EBP in Skin Carcinomas Is Linked to Oncogenic Ras and Reexpression of C/EBP in Carcinoma Cells Inhibits Proliferation

Cell Signaling and Cancer Group, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina

Requests for reprints: Robert C. Smart, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633. Phone: 919-515-7245; Fax: 919-515-7169; E-mail: rcsmart{at}unity.ncsu.edu.

The basic leucine zipper transcription factor, CCAAT/enhancer binding protein (C/EBP) is involved in mitotic growth arrest and has been implicated as a human tumor suppressor in acute myeloid leukemia. We have previously shown that C/EBP is abundantly expressed in mouse epidermal keratinocytes. In the current study, the expression of C/EBP was evaluated in seven mouse skin squamous cell carcinoma (SCC) cell lines that contain oncogenic Ha-Ras. C/EBP mRNA and protein levels were greatly diminished in all seven SCC cell lines compared with normal primary keratinocytes, whereas C/EBPß levels were not dramatically changed. Reexpression of C/EBP in these SCC cell lines resulted in the inhibition in SCC cell proliferation. To determine whether the decrease in C/EBP expression observed in the SCC cell lines also occurred in the carcinoma itself, immunohistochemical staining for C/EBP in mouse skin SCCs was conducted. All 14 SCCs evaluated displayed negligible C/EBP protein expression and normal C/EBPß levels compared with the epidermis and all 14 carcinomas contained mutant Ras. To determine whether oncogenic Ras is involved in the down-regulation of C/EBP, BALB/MK2 keratinocytes were infected with a retrovirus containing Ras12V, and C/EBP protein, mRNA and DNA binding levels were determined. Keratinocytes infected with the retrovirus containing oncogenic Ras12V displayed greatly diminished C/EBP protein, mRNA and DNA binding levels. In addition, BALB/MK2 cells containing endogenous mutant Ras displayed diminished C/EBP expression and the ectopic expression of a dominant-negative RasN17 partially restored C/EBP levels in these cells. These results indicate that oncogenic Ras negatively regulates C/EBP expression and the loss of C/EBP expression may contribute to the development of skin SCCs.

Key Words: C/EBP • Ras • keratinocytes • skin

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