Altered surface expression and increased turnover of the alpha6beta4 integrin in an undifferentiated carcinoma.
The integrin alpha6beta4, predominantly expressed on tissues of epithelial origin, is known to be variably expressed on carcinomas. The biochemical changes resulting in altered expression during tumor progression are unknown. We have analyzed the expression of alpha6beta4 in a multi-step mouse model of skin carcinogenesis representing normal keratinocyte, benign papilloma and malignant undifferentiated carcinoma. All cell lines expressed the alpha6 integrin exclusively as the alpha6beta4 integrin heterodimer. Analysis of this integrin by flow cytometry and immunoprecipitation of surface labeled proteins revealed that the undifferentiated carcinoma cells have an approximately 75% reduction in surface expression of the integrin as compared with the keratinocyte and papilloma cell lines. The alpha6beta4 integrin which remains expressed on the carcinoma cells is diffusely distributed in the membrane and has an approximately 2.5-fold increased biological turnover as compared with normal keratinocytes. The decreased biological half-life and the loss of polarized expression of alpha6beta4 on the carcinoma cells suggests an altered functional role for the alpha6beta4 integrin on carcinoma cells during tumor progression. These factors may contribute to the known supression of hemidesmosome structures and the increased migration phenotype associated with some epithelial carcinomas.
Witkowski
C M
CM
Department of Radiation Oncology and Department of Pathology, The University of Arizona Cancer Center, Tucson, AZ 85724-5024, USA.
Bowden
G T
GT
Nagle
R B
RB
Cress
A E
AE
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002465:Cell Movement; D016764:Cell Polarity; D018450:Disease Progression; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D015972:Gene Expression Regulation, Neoplastic; D006207:Half-Life; D039161:Integrin alpha6beta4; D016023:Integrins / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000378:metabolism*; D010212:Papilloma / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D013499:Surface Properties; D014407:Tumor Cells, Cultured
D000954:Antigens, Surface; D039161:Integrin alpha6beta4; D016023:Integrins; D008565:Membrane Proteins; D009363:Neoplasm Proteins