HMGI-C和HMGI(Y)基因在子宫肌瘤中的表达

目的:研究HMGI-C、HMGI(Y)基因在子宫肌瘤及子宫肌层中的表达。方法:采用Real-timePCR、Westernblot、免疫组化方法检测HMGI-C、HMGI(Y)基因在30例子宫肌瘤患者的肌瘤组织和子宫肌层组织中的表达。结果:HMGI-CmRNA及蛋白在肌瘤组织中的表达显著高于肌层组织(P<0.01)。HMGI(Y)mRNA在肌瘤组织与肌层组织中的表达无统计学差异(P>0.05),而HMGI(Y)蛋白在肌瘤组织中的表达显著高于肌层组织(P<0.05)。结论:HMGI-C、HMGI(Y)基因的异常表达与子宫肌瘤的发生有关。     

The expression and potential regulatory function of microRNAs in the pathogenesis of leiomyoma

Leiomyomas are benign uterine tumors considered to arise from transformation of myometrial cells. What initiates the conversion of myometrial cells into leiomyoma is unknown, however cytogenetic analysis often shows occurrence of nonrandom chromosomal abnormalities that may account for their establishment. It is clear that ovarian steroids are essential for leiomyoma growth, and local expression of many autocrine/paracrine mediators serving as key regulators of cell-cycle progression, cellular hypertrophy, extracellular matrix accumulation, and apoptosis appear to play central roles in this capacity. However, the stability of the expression of these genes represents the hallmarks of leiomyoma establishment, growth, and regression. With the emergence of microRNA (miRNA) as a key regulator of gene expression stability, in this review we present evidence for the expression and potential regulatory functions on miRNAs in leiomyoma with particular emphasis on the expression of their selective target genes whose products influence various cellular activities critical to pathogenesis of leiomyomas.     

Quercetin and indole-3-carbinol inhibit extracellular matrix expression in human primary uterine leiomyoma cells

Research questionWhat is the effect of quercetin and indole-3-carbinol (I3C) on extracellular matrix expression, cell migration and proliferation in human myometrial and uterine leiomyoma cells.DesignMyometrial and leiomyoma cells were treated with quercetin or I3C at different concentrations (10 µg/ml; 50 µg/ml; 100 µg/ml; and 250 µg/ml) for 48 h to measure mRNA and protein expressions of extracellular matrix (collagen 1A1, fibronectin and versican), as well as cell migration and the proliferation rate.ResultsQuercetin decreased mRNA levels of collagen 1A1 in myometrial (P < 0.0001) and leiomyoma cells (P < 0.0001). Quercetin reduced mRNA and protein levels of fibronectin in myometrial cells (P < 0.05) and fibronectin protein in leiomyoma cells (P < 0.05). I3C reduced collagen 1A1 mRNA levels in myometrial (P < 0.05) and leiomyoma cells at higher dose (P < 0.05). The protein levels of fibronectin were also reduced in both myometrial and leiomyoma cells with highest dose of I3C (P < 0.05), although mRNA levels were not affected in leiomyoma cells. Neither quercetin nor I3C treatment altered versican mRNA levels in both cell types. A significant reduction of the migration of both myometrial and leiomyoma cells in response to quercetin was observed (P < 0.05) and I3C (P < 0.05 for myometrial and P < 0.01 for leiomyoma cells) treatment. Both quercetin and I3C significantly reduced myometrial cell proliferation (P < 0.05).ConclusionsThe in-vitro anti-fibrotic, anti-migratory and anti-proliferative effects of quercetin and I3C form the scientific basis for developing new therapeutic, preventive agents, or both, for uterine leiomyomas.     

The difference in sex hormone dependence for gap junction formation in the muscles of uterine leiomyoma and normal myometrium

Gap junction is reported to be initiated by changes in levels of steroid hormones in the smooth muscle cells of myometrium. In order to clarify the difference in sex hormone dependence for gap junction formation in the muscles of uterine leiomyoma and normal myometrium, uterine leiomyoma and myometrial gap junctions, and serum estradiol and progesterone levels were determined simultaneously in 23 women who had undergone simple hysterectomy for leiomyomas of the corpus uteri. In all tissues of the myometrium from 23 women, at least three gap junctions were found between muscle cells in the series of photographs. On the other hand, there were 7 out of 23 uterine leiomyomas in which not even one gap junction was detected between muscle cells in the series of photographs. The phasic change in the number of gap junctions related to the menstrual cycle was detected in the muscles of uterine leiomyoma as well as normal myometrium. Uterine leiomyoma was characterized by less correlation between the number of gap junctions in the muscles and the concentration of serum sex steroids, compared with those of normal myometrium. Sex steroids may have a trophic effect on some uterine leiomyoma, but the sex hormone dependence of uterine leiomyoma for gap junction formation may be less than that of normal myometrium. The present study also showed that the increased gap junction formation in myometrial muscles from women with dysmenorrhea may be formed between myometrial cells in response to physiologic or pathologic stimuli, such as the production of local prostaglandins, and may result in hypercontraction of the uterus.     

Growth potential of human uterine leiomyomas: some in vitro observations and their implications

Tissue culture techniques commonly applied to the study of human vascular smooth muscle were used to evaluate in vitro survival and proliferation of normal and neoplastic human myometrial cells. Despite their growth advantage in vivo, leiomyoma cells displayed a growth disadvantage in vitro compared with normal myometrium from the same patient. Hormonal supplementation with alpha-estradiol, progesterone, and insulin-stimulated myometrial proliferation, whereas beta-estradiol appeared ineffective at the doses tested. Hormonal supplementation also stimulated leiomyoma proliferation in vitro, but there appeared to be heterogeneity in hormonal responsiveness. Heterogeneity in the host hormonal milieu and in the ability of uterine leiomyomas to respond to various hormones may be important factors contributing to the wide variation in growth potential observed in leiomyomas.     

Aldosterone stimulates the proliferation of uterine leiomyoma cells

Objective.?Although uterine leiomyomas are the most common gynaecological benign tumour and greatly affect reproductive health and well being, the pathophysiology and epidemiology of uterine leiomyomas are not well known. Elevated blood pressure has an independent, positive association with risk for clinically detected uterine leiomyomas. Aldosterone is a key biological peptide in the renin-angiotensin-aldosterone system that regulates blood pressure. In this study, we investigated the siginificant stimulatory effect of aldosterone on leiomyoma cells proliferation.

Study design.?This study investigated the potential role of aldosterone in the proliferation of ELT-3 leiomyoma cells.

Results.?Aldosterone-induced ELT-3 leiomyoma cell proliferation and the expression of mineralocorticoid receptor (MR) were confirmed. Pre-incubating the cells with the MR blockers spironolactone or eplerenone effectively repressed aldosterone-induced and angiotensin II (Ang II)-induced cell proliferation. Treatment of aldosterone increased the levels of Ang II type-1 receptor mRNA.

Conclusion.?These experimental findings in?vitro show the presence of complex regulation of Ang II and aldosterone induced leiomyoma cell proliferation.     

Transforming growth factor-beta3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation

OBJECTIVE: To investigate the expression of TGF-beta3 in leiomyoma and myometrium as well as the effect of TGF-beta3 on the expression of fibronectin and on the proliferation of leiomyoma and myometrial cells. DESIGN: Observational and in vitro experimental study. SETTING: University medical center.Patient(s): Women with (n = 18) leiomyoma. INTERVENTION(s): First TGF-beta3 mRNA and protein levels in myometrium and leiomyoma were measured, and then myometrial and leiomyoma cells in culture were treated with TGF-beta3. MAIN OUTCOME MEASURE(s): TGF-beta3 and fibronectin mRNA were evaluated by Northern analysis. Myometrial and leiomyoma cell proliferation was assessed with use of [(3)H]thymidine incorporation. RESULT(s): The TGF-beta3 mRNA level in the leiomyoma samples was 3.5-fold higher than in the myometrial samples. The highest TGF-beta3 mRNA level was observed in leiomyoma samples from midsecretory phase and was 5-fold higher than in proliferative phase samples. Fibronectin mRNA expression also was higher in the leiomyoma than in the myometrium. TGF-beta3 induced fibronectin expression in leiomyoma cells and directly stimulated myometrial and leiomyoma cell proliferation in cultures. CONCLUSION(s): These findings suggest that TGF-beta3 may be mediating the growth-promoting effects of sex steroids on leiomyomas by playing a role in the fibrogenic process and cell proliferation that characterize these tumors.     

Leiomyomas in uterine remnants associated with vaginal agenesis

A premenopausal woman with vaginal agenesis underwent surgery for leiomyomas in rudimentary uterine horns. Immunohistochemical study of surgical specimens revealed that progesterone receptors are distributed in the nuclei of a majority of the leiomyoma cells and in the nuclei of a minority of the myometrial cells. Estrogen receptors are not detected in the surgical specimens. Copyright Copyright 1999 S. Karger AG, Basel     

Pseudo-Meigs' syndrome caused by a hydropic degenerating uterine leiomyoma with elevated CA 125

BACKGROUND: Uterine leiomyomas rarely cause pseudo-Meigs' syndrome with elevated serum CA 125 levels. CASE: A 39-year-old patient with a large uterine leiomyoma is described. The associated massive ascites, pleural fluid, and increased CA 125 level all seemed to be related to the uterine tumor. Hydropic degenerating leiomyomas are characterized by focal accumulation of edema and collagen deposition. Marked degrees of hydropic degeneration may have resulted in cystic degeneration, leading to large myometrial cysts. A presumed direct relation between the abundance of intratumoral fluid and presence of ascites seemed justified. The increased level of CA 125 most probably resulted from the peritoneal mechanical irritation from the large leiomyoma or from a large volume of ascites. Having accumulated a sufficient volume and pressure, the ascites finds it way through the diaphragm through intercellular gaps and diaphragmatic apertures, as well as through small bilateral areas where muscular tissue of the diaphragm is replaced by areolar tissue, resulting in the presence of pleural fluid. CONCLUSION: The pathophysiology of a uterine leiomyoma mimicking a pelvic malignancy is described.     

Uterine leiomyomas express myometrial contractile-associated proteins involved in pregnancy-related hormone signaling

We used an animal model to study uterine leiomyoma in the context of pregnancy-associated changes in gene expression and to determine how they might modulate tumor growth.Spontaneous tumors and normal myometrium were collected from Eker rats and compared with myometrial samples from pregnant animals. A leiomyoma-derived cell line was also used to assess pregnancy-related changes in gene expression and to determine the impact of signaling by the oxytocin receptor.Eker rat leiomyomas expressed several pregnancy-related genes, including connexin 43, oxytocin receptor (OTR), and cyclooxygenase (COX)-1; however, the tumors did not express COX-2, which is expressed in the parturient myometrium. The leiomyoma-derived cell lines also expressed OTR, which responds to estrogen, binds to oxytocin, and exhibits a calcium flux when stimulated with oxytocin. The OTR signaling mediated by oxytocin inhibited estrogen-stimulated growth of leiomyoma cells.Leiomyoma cells expressed many genes of the parturient myometrium, including OTRs, but were deficient in COX-2 expression. Signaling via the OTR appears to inhibit estrogen-induced cell proliferation, suggesting that signaling by this receptor might help mediate the protective effect of pregnancy on this disease.     

Insulin-like growth factor I promotes leiomyoma cell growth in vitro

Objective: Our purpose was to determine whether insulin-like growth factors I and II preferentially stimulate uterine leiomyoma cells versus myometrial cells in monolayer culture.Study design: Leiomyomas and normal myometrium were obtained at hysterectomy from five premenopausal women. Specimens were enzymatically digested for use in primary monolayer cell cultures. By use of serum-free media, insulin-like growth factor I or II was added in 1, 10, and 100 ng/ml concentrations to both cell types with the patient serving as her own control. Cell number, prolactin production, and proliferative index values were measured on day 15 of cell culture.Results: Significant increases in cell number were found in the leiomyoma cultures (p < 0.05) treated with 10 and 100 ng/ml insulin-like growth factors I but not with insulin-like growth factos II. Neither factor exerted a stimulatory effect on myometrial cells.Conclusion: Insulin-like growth factor sI preferentially stimulates leiomyoma cells in monolayer culture. These results suggest an autocrine-paracine role in vivo for this factor in conjuction with gonadal steroids in promoting leiomyoma growth.