A SPLICE VARIANT OF ALPHA-6 INTEGRIN IS ASSOCIATED WITH MALIGNANT CONVERSION IN MOUSE SKIN TUMORIGENESIS

The epithelial-specific integrin alpha 6 beta 4 is suprabasally expres sed in benign skin tumors (papillomas) and is diffusely expressed in c arcinomas associated with an increase in the proliferating compartment . Analysis of RNA samples by reverse transcriptase-PCR and DNA sequenc ing revealed that chemically or oncogenically induced papillomas (n = 8) expressed a single transcript of the alpha 6 subunit, identified as the alpha 6A splice variant. In contrast, carcinomas (n = 13) express ed both alpha 6A and an alternatively spliced form, alpha 6B. Primary keratinocytes and a number of keratinocyte cell lines that vary in bio logical potential from normal skin, to benign papillomas, to well-diff erentiated slowly growing carcinomas exclusively expressed (alpha 6A. However, I-7, an oncogene-induced cell line that produces highly invas ive carcinomas, expressed both alpha 6A and alpha 6B transcript and pr otein, The expression of alpha 6B in I-7 cells was associated with inc reased attachment to a laminin matrix compared to cell lines exclusive ly expressing alpha 6A. Furthermore, introduction of an alpha 6B expre ssion vector into a papilloma cell line expressing alpha 6A increased laminin attachment. When a papilloma cell line was converted to an inv asive carcinoma by introduction of the v-fos oncogene, the malignant c ells expressed both alpha 6A and alpha 6B, while the parent cell line and cells transduced with v-jun or c-myc, which retained the papilloma phenotype, expressed only alpha 6A. Comparative analysis of alpha 6B expression in cell lines and their derived tumors indicate that alpha 6B transcripts are more abundant in tumors than cell lines, and alpha 6B is expressed to a greater extent in poorly differentiated tumors. T hese results establish a link between malignant conversion and invasio n of squamous tumor cells and the regulation of transcript processing of the alpha 6 beta 4 integrin.