Wei Tao, Geiser Andrew G, Qian Hui-Rong, Su Chen, Helvering Leah M, Kulkarini Nalini H, Shou Jianyong, N'Cho Mathias, Bryant Henry U, Onyia Jude E
Integrative Biology, Lilly Research Laboratories, Greenfield, Indiana 46140, USA.
BMC Womens Health. 2007 Apr 2;7:5. doi: 10.1186/1472-6874-7-5.
Uterine 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.
Differentially 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.
By 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 PPARgamma 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 PPARgamma. 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.
Integrated 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.
子宫肌瘤或平滑肌瘤是常见的良性平滑肌肿瘤。众所周知，肿瘤生长依赖雌激素。然而，其雌激素依赖性的分子机制尚不清楚。
人类子宫肌瘤中差异表达的基因，要么从已发表的论文中获取，要么来自我们对下载的阵列数据的统计分析。基于Affymetrix提供的探针比较信息，对不同Affymetrix芯片上相同基因的探针进行映射。将通过两项或三项阵列研究鉴定出的基因提交进行直系同源分析。使用直系同源基因数据库HomoloGene和TOGA鉴定人类和大鼠的直系同源基因，并通过Ensembl基因组浏览器中的MultiContigView工具进行同线性分析来确认。
通过对三项最近发表的人类组织DNA微阵列研究进行综合分析，发现至少两个研究小组发现有38个基因在子宫肌瘤中与相邻子宫肌层相比以相同方向差异表达。在这些基因中，我们在研究用雌激素处理的去卵巢大鼠子宫表达的阵列研究中，将12个具有大鼠直系同源基因的基因鉴定为受雌激素调节。对这12个基因的功能和通路分析表明，雌激素依赖性细胞存活和肿瘤生长存在多种分子机制。首先，雌激素增加抗凋亡PCP4基因的表达，并抑制生长抑制受体PTGER3和TGFBR2的表达。其次，雌激素可能在PPAR途径的两个点拮抗被认为抑制肌瘤生长和存活的PPARγ信号：1）通过增加可抑制磷脂酶A2活性进而减少花生四烯酸合成的ANXA1基因表达，以及2）通过降低L-PGDS表达，这将减少PPARγ的内源性配体PGJ2的合成。最后，雌激素通过调节CRABP2和ALDH1A1的表达来影响视黄酸（RA）的合成和转运。在动物模型中，RA已被证明在子宫肌瘤的发展中起重要作用。
多个阵列数据集的综合分析揭示了12个人类和大鼠直系同源基因，它们在人类子宫肌瘤中差异表达，并在大鼠子宫中转录响应雌激素。对这些基因的功能和通路分析表明，对于理解不足的子宫肌瘤雌激素依赖性生长存在多种潜在分子机制。要完全了解这些基因产物之间的确切分子相互作用，需要进一步研究以验证它们在子宫肌瘤中的作用。这项工作提供了新的研究途径，可能会影响该疾病未来治疗干预的方向。
