Expression and regulation of a molecular marker, SPR1, in multistep bronchial carcinogenesis

A small proline-rich protein, SPR1, is overexpressed in squamous metaplasia of bronchial epithelium. We studied the expression and regulation of SPR1 in a series of human bronchial epithelial cell lines representing a model o f multistep bronchial carcinogenesis, These cell lines included a primary c ulture of tracheobronchial epithelial cells (HTBE), a papilloma virus-trans formed tracheobronchial epithelial cell line (HBE1), a cell line selected f rom HBE1 by a tobacco carcinogen and a phorbol ester (HBE1-C), a simian vir us-transformed bronchial epithelial cell line (BEAS-2B), and a lung carcino ma cell line (H460). Different tumorigenic potentials of these cell lines w ere indicated by graded levels of telomerase activity, Concomitant with squ amous transformation, there was an increase in SPR1 expression in MTBE, HBE 1, and HBE1-C that was reversible by vitamin A, With progression of tumorig enicity, there was a marked reduction in SPR1 expression in BEAS-2B and a t otal loss of expression in H460, In these latter cell lines representing ad vanced malignant transformation, there was a loss of up- and downregulation , respectively, by the phorbol ester and vitamin A. Transfection study with chimeric constructs of the SPR1 promoter and a reporter gene showed that t he dysregulation of SPR1 expression in malignant transformation was a resul t of perturbation of the basal and enhancer elements of the first 162 nucle otides in the 5'-flanking promoter region of the SPR1 gene. These findings suggest an association of transcriptional dysregulation of the SPR1 gene wi th multistep bronchial carcinogenesis.