Retinoic acid pathway genes show significantly altered expression in uterine fibroids when compared with normal myometrium.
Fibroids are benign neoplasms of myometrial smooth muscle cells (SMC). Despite being the most common tumor in humans, their etiology is poorly understood. Recent microarray studies have demonstrated that multiple members of the retinoid pathway are differentially expressed between myometrium and fibroids. The aim of this present study was to investigate gene expression of members of the retinoid pathway in matched myometrium and fibroids. We have demonstrated differential gene expression of two binding proteins [cellular retinol-binding proteins (CRBP) 1 and 2], three enzymes [alcohol dehydrogenase 1 (ADH1), aldehyde dehydrogenase (ALDH1) and retinol dehydrogenase (RODH)] and two receptors [retinoid X receptors (RXR) alpha and gamma] involved in the retinoid pathway by real-time PCR. There were no differences in gene expression for retinoid receptors RARalpha, beta, gamma and RXRbeta, and for the metabolizing enzyme cytochrome P450, family 26 subfamily A. We confirmed results for ADH1, ALDH1, CRBP1 and CRABP2 at the protein level by western blot. Using immunohistochemistry these proteins were mostly localized to myometrial and fibroid SMC. An exception to this was ALDH1 protein, which displayed strong staining localized to cells of the connective tissue, presumably fibroblasts, with a striking differential expression pattern between myometrium and fibroids. These results demonstrate that the retinoid pathway is altered in fibroids when compared with normal myometrium and specifically identify ALDH1 in fibroid fibroblasts. These alterations can lead to aberrant retinoic acid (RA) production and signaling, and alter the expression of RA target genes, which may be an important step in fibroid development.
Zaitseva
Marina
M
Centre for Women's Health Research, Monash University Department of Obstetrics and Gynaecology, Monash Institute of Medical Research, Clayton, Victoria, Australia.
Vollenhoven
Beverley J
BJ
Rogers
Peter A W
PA
D000328:Adult; D000426:Alcohol Dehydrogenase / Q000032:analysis / Q000235:genetics; D000444:Aldehyde Dehydrogenase / Q000032:analysis / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D005260:Female; D015870:Gene Expression; D011495:Histone-Lysine N-Methyltransferase / Q000032:analysis / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics; D007889:Leiomyoma / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009215:Myometrium / Q000737:chemistry / Q000378:metabolism; D050697:Retinal Dehydrogenase; D012177:Retinol-Binding Proteins / Q000032:analysis / Q000235:genetics; D054840:Retinol-Binding Proteins, Cellular; D014212:Tretinoin / Q000378:metabolism*; D014594:Uterine Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D007527:Isoenzymes; C518456:RBP1 protein, human; C518459:RBP2 protein, human; D012177:Retinol-Binding Proteins; D054840:Retinol-Binding Proteins, Cellular; D014212:Tretinoin; D000426:Alcohol Dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D011495:Histone-Lysine N-Methyltransferase