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Malignant Human Papillomavirus Type 16-transformed Human Keratinocytes Exhibit Altered Expression of Extracellular Matrix Glycoproteins¹

Department of Pathology, University of Wisconsin, Madison, Wisconsin 53706 [N. S., B. L. A-H.], and Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892 [J. S. R.]

We found that keratinocytes immortalized with human papillomavirus (HPV) type 16 DNA and malignantly converted by H-ras transfection (HPK-1A/ras) exhibit an enhanced ability to synthesize a fibronectin-containing extracellular matrix. Gene expression of fibronectin and thrombospondin was increased in tumorigenic keratinocytes compared to control and immortalized keratinocytes, 6- and 9-fold, respectively. Increased production of soluble and cell surface-associated fibronectin was not specific for HPV 16 transformed keratinocytes. Ad12-SV40-immortalized keratinocytes malignantly converted by H-ras transfection (RHEK-1/ras) also exhibited enhanced expression of fibronectin and thrombospondin, as well as pro-1 type I collagen. Steady state mRNA levels for autocrine growth-regulatory factors, transforming growth factors and ß1, were increased in Ad12-SV40 but not HPV 16-transformed human keratinocytes. We then determined whether increased production of fibronectin was associated with aberrant differentiation of transformed keratinocytes. Less than 10% of the HPV 16-transformed cells produced cornified envelopes after suspension-induced differentiation compared to 70% of normal keratinocytes. However, immortalization by HPV 16 DNA was sufficient to confer a differentiation-defective phenotype. Both involucrin mRNA and protein levels were decreased 8-fold in HPV 16-immortalized keratinocytes compared to normal cells and malignant conversion further attenuated involucrin levels. These studies demonstrate that aberrant differentiation is an early event in the transformation of the human keratinocytes and is not the result of enhanced expression of the extracellular matrix proteins. Unlike transformed fibroblastic cell types, up-regulation of fibronectin gene expression and matrix formation is a consistent characteristic of malignantly converted human keratinocytes.

¹ This work was supported by Grant R29 AR40284 (to B. L. A-H.); N. S. is a trainee on Grant HD07118 from the NIH.

² To whom requests for reprints should be addressed, at 5638 Medical Sciences Center, 1300 University Avenue, Madison, WI 53706.

Received 5/28/91. Accepted 8/27/91.

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