A splice variant of α6 integrin is associated with malignant conversion in mouse skin tumorigenesis

摘要

The epithelial-specific integrin α6β4 is su-prabasally expressed in benign skin tumors (papillomas) and is diffusely expressed in carcinomas associated with an increase in the proliferating compartment. Analysis of RNA samples by reverse transcriptase-PCR and DNA sequencing revealed that chemically or oncogenically induced papillomas (n = 8) expressed a single transcript of the α6 subunit, identified as the α6A splice variant. In contrast, carcinomas (n = 13) expressed both α6A and an alternatively spliced form, α6B. Primary keratinocytes and a number of keratino-cyte cell lines that vary in biological potential from normal skin, to benign papillomas, to well-differentiated slowly growing carcinomas exclusively expressed α6A. However, I_7, an oncogene-induced cell line that produces highly invasive carcinomas, expressed both α6A and α6B transcript and protein. The expression of α6B in I_7 cells was associated with increased attachment to a laminin matrix compared to cell lines exclusively expressing α6A. Furthermore, introduction of an α6B expression vector into a papilloma cell line expressing α6A increased laminin attachment. When a papilloma cell line was converted to an invasive carcinoma by introduction of the v-fos oncogene, the malignant cells expressed both α6A and α6B, while the parent cell line and cells transduced with v-jun or c-myc, which retained the papilloma phenotype, expressed only α6A. Comparative analysis of α6B expression in cell lines and their derived tumors indicate that α6B transcripts are more abundant in tumors than cell lines, and α6B is expressed to a greater extent in poorly differentiated tumors. These results establish a link between malignant conversion and invasion of squamous tumor cells and the regulation of transcript processing of the α6β4 integrin.