Abstract
BackgroundUterine fibroids or leiomyoma are a common benign smooth muscle tumor. The tumor growth is well known to be estrogen-dependent. However, the molecular mechanisms of its estrogen-dependency is not well understood.MethodsDifferentially expressed genes in human uterine fibroids were either retrieved from published papers or from our own statistical analysis of downloaded array data. Probes for the same genes on different Affymetrix chips were mapped based on probe comparison information provided by Affymetrix. Genes identified by two or three array studies were submitted for ortholog analysis. Human and rat ortholog genes were identified by using ortholog gene databases, HomoloGene and TOGA and were confirmed by synteny analysis with MultiContigView tool in the Ensembl genome browser.ResultsBy integrated analysis of three recently published DNA microarray studies with human tissue, thirty-eight genes were found to be differentially expressed in the same direction in fibroid compared to adjacent uterine myometrium by at least two research groups. Among these genes, twelve with rat orthologs were identified as estrogen-regulated from our array study investigating uterine expression in ovariectomized rats treated with estrogen. Functional and pathway analyses of the twelve genes suggested multiple molecular mechanisms for estrogen-dependent cell survival and tumor growth. Firstly, estrogen increased expression of the anti-apoptotic PCP4 gene and suppressed the expression of growth inhibitory receptors PTGER3 and TGFBR2. Secondly, estrogen may antagonize PPARγ signaling, thought to inhibit fibroid growth and survival, at two points in the PPAR pathway: 1) through increased ANXA1 gene expression which can inhibit phospholipase A2 activity and in turn decrease arachidonic acid synthesis, and 2) by decreasing L-PGDS expression which would reduce synthesis of PGJ2, an endogenous ligand for PPARγ. Lastly, estrogen affects retinoic acid (RA) synthesis and mobilization by regulating expression of CRABP2 and ALDH1A1. RA has been shown to play a significant role in the development of uterine fibroids in an animal model.ConclusionIntegrated analysis of multiple array datasets revealed twelve human and rat ortholog genes that were differentially expressed in human uterine fibroids and transcriptionally responsive to estrogen in the rat uterus. Functional and pathway analysis of these genes suggest multiple potential molecular mechanisms for the poorly understood estrogen-dependent growth of uterine fibroids. Fully understanding the exact molecular interactions among these gene products requires further study to validate their roles in uterine fibroids. This work provides new avenues of study which could influence the future direction of therapeutic intervention for the disease.
Highlights
Uterine fibroids or leiomyoma are a common benign smooth muscle tumor
Understanding the exact molecular interactions among these gene products requires further study to validate their roles in uterine fibroids
Identification of human and rat ortholog genes that are estrogen responsive and differentially expressed in uterine fibroids Figure 1 shows the procedure that was employed to identify human and rat ortholog genes that were differentially expressed in human uterine fibroids and estrogen-regulated in rat uterus
Summary
Uterine fibroids or leiomyoma are a common benign smooth muscle tumor. Leiomyoma or uterine fibroids are the most common benign tumor, occurring in approximately 60% of women during their lifetime[1]. The etiology of the disease is largely unknown, it is clear that growth of uterine fibroids depends on the ovarian hormones estrogen and progesterone [2]. This hormonal dependency is supported by the following observations. Evidence shows that one effect of estrogen is to increase the levels of both estrogen receptor (ER) and progesterone receptor (PR) [2]. It has been recently demonstrated that estrogen can stabilize ER mRNA, increasing the level of cellular ER protein [8]
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