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Molecular and Cellular Biology, December 1998, p. 7095-7105, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Fra-1 Induces Morphological Transformation and Increases In Vitro Invasiveness and Motility of Epithelioid Adenocarcinoma Cells

Olga Kustikova,1,dagger Dmitrii Kramerov,1,Dagger Mariam Grigorian,1 Vladimir Berezin,2 Elisabeth Bock,2 Eugene Lukanidin,1 and Eugene Tulchinsky1,*

Department of Molecular Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen Ø,1 and Protein Laboratory, Institute of Molecular Pathology, Copenhagen University, DK-2200 Copenhagen N,2 Denmark

Received 6 April 1998/Returned for modification 1 June 1998/Accepted 28 August 1998

Two cell lines originating from a common ancestral tumor, CSML0 and CSML100, were used as a model to study AP-1 transcription factors at different steps of tumor progression. CSML0 cells have an epithelial morphology; they express epithelial but not mesenchymal markers and are invasive neither in vitro nor in vivo. CSML100 possesses all characteristics of a highly progressive carcinoma. These cells do not form tight contacts, are highly invasive in vitro, and are metastatic in vivo. AP-1 activity was considerably higher in CSML100 cells than in CSML0 cells. There was a common predominant Jun component, namely, JunD, detected in both cell lines. We found that the enhanced level of AP-1 in CSML100 cells was due to high expression of Fra-1 and Fra-2 proteins, which were undetectable in CSML0 nuclear extracts. Analysis of the transcription of different AP-1 members in various cell lines derived from tumors of epithelial origin revealed a correlation of fra-1 expression with mesenchymal characteristics of carcinoma cells. Moreover, we show here for the first time that the expression of exogenous Fra-1 in epithelioid cells results in morphological changes that resemble fibroblastoid conversion. Cells acquire an elongated shape and become more motile and invasive in vitro. Morphological alterations were accompanied by transcriptional activation of certain genes whose expression is often induced at late stages of tumor progression. These data suggest a critical role of the Fra-1 protein in the development of epithelial tumors.

* Corresponding author. Mailing address: Department of Molecular Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark. Phone: 45 352 57312. Fax: 45 35257721. E-mail: et{at}cancer.dk.

dagger Present address: Institute for Gene Biology, Russian Academy of Sciences, Moscow, Russia.

Dagger Present address: Institute for Molecular Biology, Russian Academy of Sciences, Moscow, Russia.

Molecular and Cellular Biology, December 1998, p. 7095-7105, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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