Objective: To analyze expression of the retinoic acid signaling pathway genes that are involved in retinol metabolism, transport, transcriptional activation, and transcriptional products in spontaneous human leiomyomas.
Design: Laboratory study of human leiomyoma and patient-matched myometrial tissue.
Patient(s): Eight women undergoing hysterectomy for symptomatic leiomyomas.
Intervention(s): Confirmation of an altered retinoic acid pathway analyzed by microarray, real time reverse transcription-polymerase chain reaction, Western blot, immunohistochemistry, and high-performance liquid chromatography (HPLC).
Main outcome measure(s): Gene and protein expression.
Result(s): Regardless of patient demographics and leiomyoma location and size, we found decreased expression of the major genes involved in retinoic acid pathway including alcohol dehydrogenase-1 (-3.97- +/- 0.03-fold), aldehyde dehydrogenase-1 (-3.1- +/- 0.07-fold), cellular retinol binding protein-1 (-2.62- +/- 0.04-fold), and cellular retinoic acid binding protein-1 (-2.42- +/- 0.20-fold). Cytochrome P450 (CYP 26A1), which is responsible for retinoic acid metabolism, was highly up-regulated in leiomyomas (+5.4- +/- 0.53-fold). Nuclear receptors demonstrated a complex pattern of under-expression (RARalpha, RARbeta, RXRalpha, RXRgamma) and over-expression (RARgamma, RXRbeta) at both the mRNA and protein level. Differences in protein amounts were confirmed by Western blot. Finally, a reduced amount of cellular ATRA and 9-cis retinoic acid was confirmed by HPLC in leiomyomas compared with myometrial tissues.
Conclusion(s): Molecular alterations in the retinoic acid pathway of leiomyomata result in a decrease in retinoic acid exposure.