Gene expression profiling of multiple leiomyomata uteri and matched normal tissue from a single patient

Abstract

Objective-To identify differentially expressed genes between fibroid and adjacent normal myometrium in an identical hormonal and genetic background.Design-Array analysis of 3 leiomyomata and matched adjacent normal myometrium in a single patient. Setting-University of Colorado Hospital.Patient(s)-A single female undergoing medically indicated hysterectomy for symptomatic fibroids.Interventions(s)-mRNA isolation and microarray analysis, reverse-transcriptase polymerase chain reaction, western blotting and immunohistochemistry.Main Outcome Measure(s)-Changes in mRNA and protein levels in leiomyomata and matched normal myometrium.Result(s)-Expression of 197 genes was increased and 619 decreased, significantly by at least 2 fold, in leiomyomata relative to normal myometrium. Expression profiles between tumors were similar and normal myometrial samples showed minimal variation. Changes in, and variation of, expression of selected genes were confirmed in additional normal and leiomyoma samples from multiple patients. Conclusion(s)-Analysisof multiple tumors from a single patient confirmed changes in expression of genes described in previous, apparently disparate, studies and identified novel targets. Gene expression profiles in leiomyomata are consistent with increased activation of mitogenic pathways and inhibition of apoptosis. Down-regulation of genes implicated in invasion and metastasis, of cancers, was observed in fibroids. This expression pattern may underlie the benign nature of uterine leiomyomata and may aid in the differential diagnosis of leiomyosarcoma.

An Integrative Genomic and Transcriptomic Analysis Reveals Potential Targets Associated with Cell Proliferation in Uterine Leiomyomas

“…In addition, cellular proliferation stimulated by growth factors and/or steroid hormones is one of the mechanisms associated with the increased tumour volume observed in ULs [42], [43]. The COL3A1 , IGFBP5 and FGFR1 genes are directly associated with the typical features found in ULs (including fibroid formation), which strongly suggests their involvement in ULs pathogenesis.…”

Development and validation of a three-dimensional in vitro model for uterine leiomyoma and patient-matched myometrium

“…What distinguishes the leiomyomata from its surrounding myometrium is the excessive and disorganized ECM that surrounds the cells. The excessive ECM secreted by the leiomyoma cells in vivo is supported by the altered expression of the genes specific to these ECM proteins, as compared with the myometrium (1,(22)(23)(24)(25)(26). We have demonstrated that the immortalized myometrium and leiomyoma cells, when grown in 3D collagen-1 culture, retain the in vivo characteristics of the tissues they are derived from as well as the characteristic spindle shape of the SMC.…”

Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids

“…Although a large number of genes are differentially expressed in fibroids compared with myometrium (Tsibris et al 2002, Skubitz & Skubitz 2003, Arslan et al 2005, Luo et al 2005a, 2005b, Zaitseva et al 2006, Dimitrova et al 2009, it is likely that most of these changes occur as a consequence of the fibroids' presence and do not cause fibroid development. We have targeted NR2F2 and CTNNB1 in this study based on their significant potential for a causal role in uterine fibroid pathophysiology , Tanwar et al 2009).…”

“…Currently, uterine fibroids are the single-most common reason for hysterectomy in developed countries (Treloar et al 1999, Farquhar & Steiner 2002, Garry 2005, and despite their large healthcare burden, there is limited understanding of the molecular mechanisms that drive fibroid pathophysiology. Gene profiling studies by our laboratory and others have identified a large number of genes with altered expression in fibroid tumours compared with myometrium (Tsibris et al 2002, Skubitz & Skubitz 2003, Arslan et al 2005, Luo et al 2005a, 2005b, Zaitseva et al 2006, Dimitrova et al 2009). However, it is hypothesised that the majority of these genes are differentially expressed as a consequence of the changed microenvironment caused by the fibroids' presence and are not causal to fibroid development.…”