Retinoids regulate genes involved in retinoic acid synthesis and transport in human myometrial and fibroid smooth muscle cells

Abstract

Despite the fact that uterine fibroids are the most common benign tumors in women, their etiology is poorly understood. We have previously shown that multiple members of the retinoic acid (RA) pathway have altered expression in fibroids compared with normal myometrium. The aims of the present study were: to investigate regulation of genes involved in the RA pathway in vitro; and to identify genes that can be used as markers to distinguish myometrial and fibroid smooth muscle cells in culture. We demonstrate here for the first time that differential expression of aldehyde dehydrogenase 1 (ALDH1) between fibroids and myometrium is maintained in cell culture (without endothelial cells), and that this gene is differentially regulated by retinoids in myometrial compared with fibroid cells. RA and retinol also regulate expression of ADH1, cellular retinol binding protein 1 and cellular RA binding protein 2 in fibroid and myometrial cells. We show that many of the RA pathway genes tested maintain expression levels and differences in vitro. We also identify nine genes that are differentially expressed between myometrium and fibroids and maintain these differences and expression levels in cultured cells isolated from the same tissues. These genes can be used as markers to distinguish myometrial and fibroid cells in culture. Based on these findings, we propose that the RA pathway has an important and possible causative role in fibroid growth, as evidenced by the large number of genes with significantly altered expression in uterine fibroids that can be regulated by RA.