Molecular mechanisms involved in the growth of human uterine leiomyomas

University dissertation from Stockholm : Karolinska Institutet, Department of Clinical Sciences

Abstract: Human uterine leiomyomas (fibroids) are benign neoplasms arising from uterine smooth muscle cells, and are suggested to be sex steroid dependent. The aim of this study was to investigate the molecular mechanisms by which sex steroids, mainly estrogen and progesterone, influence the growth of Ieiomyomas. The first study investigated cell proliferation and apoptosis in both leiomyoma and myometrial cells during the menstrual cycle to determine if a growth advantage existed for leiomyomas. Leiomyoma cells had significantly higher mitotic activity than myometrial cells in the secretory phase compared with the proliferative phase of the menstrual cycle, suggesting that progesterone is important for cell proliferation in leiomyomas. Apoptosis in leiomyomas is related to the function of Bcl-2 family proteins and was explored in the second study. The expression of Bcl-2 in leiomyomas was stronger than in myometrium both in the proliferative and secretory phases of the menstrual cycle. Bax immunostaining was also higher in leiomyomas than in myometrium and decreased after menopause, however the expression of other proteins in this family (Bak, Bcl-x and Mcl-1) was very diverse. In the third study we investigated expression of the progesterone receptor (PR) and local growth factor insulin-like growth factor (IGF-I). There were significant differences in mRNA and protein expression of PR and IGF-I in both myometrium and leiomyomas proliferative phase tissue compared with tissue after gonadotropin releasing hormone agonist (GnRHa) treatment. In situ hybridization revealed that IGF-I mRNA in the myometrium and leiomyomas was located in areas where the smooth muscle cells were dominant. Using representational difference analysis (RDA) of cDNA in the fourth study, we identified five candidate genes, latent transforming growth factor binding protein 2 (LT13P2), zinc finger protein (ZFP 185), tomoregulin, cellular retinoid acid binding protein 1 (CRABP1) and pregnancy-associated plasma protein A (PAPPA) with higher expression in leiomyomas than in myometrium, suggesting a potential role as growth promoters in leiomyomas. In the final study we analyzed the expression of approximately 3000 genes affected by estrogen in the rat uterus by using cDNA-microarray. Five interesting genes were putatively estrogen-responsive in the uterus, including Fas-activated serine/threonine kinase (FAST), CD24, thymosin beta4, follistatin-related protein (FSRP) and thy-1 protein. We hypothesize that the Fas/Fas-L pathway and CD24 may be important during the cellular processes in the uterus influenced by estrogen. Gene expression profiling provides a unique opportunity for understanding the molecular mechanisms of estrogen actions in uterus. In conclusion, there exists a selective growth advantage for leiomyomas involving a complex of factors regulated by the sex steroid hormones whose actions are very universe.

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