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Overexpression of the Wnt5b Gene in Leiomyoma Cells: Implications for a Role of the Wnt Signaling Pathway in the Uterine Benign Tumor

Department of Obstetrics, Gynaecology and Neonatology (S.M., P.V., D.L., A.A.), The "L. Mangiagalli" Hospital; Department of Obstetrics and Gynaecology, Clinica "Macedonio-Melloni" (M.V.) and Istituto Auxologico Italiano (A.M.D.B.), Cusano Milanino 20095, Italy

Address all correspondence and requests for reprints to: Dr. A. M. Di Blasio, Molecular Biology Laboratory, Istituto Auxologico Italiano, Via Zucchi 18, Cusano Milanino 20095, Italy. E-mail: a.diblasio{at}auxologico.it.

Context: Uterine leiomyomas are the most common tumors in the human female pelvis and the leading indication for pelvic surgery. The molecular causes of the disease remain unknown.

Objective: Using an oligonucleotide microarray-based hybridization analysis, we observed that a Wnt family member transcript, Wnt5b, was overexpressed in smooth muscle cells (SMC) derived from leiomyomas when compared with matched myometrial cells. Based on this finding and on previous observations, we have hypothesized that altered expression of specific Wnt family members might be involved in leiomyoma formation and/or growth.

Main Outcome Measures: The expression patterns of two members of the Wnt pathway, Wnt5b and secreted frizzled related protein (sFRP)1, were evaluated in myometrial SMC (n = 22) and in leiomyoma cells (n = 27) by real-time quantitative PCR. In addition, regulation of expression of the two molecules was examined.

Results: Compared with myometrial SMC, cells derived from leiomyomas had significantly higher levels of both Wnt5b and sFRP1 transcripts. When the data were analyzed as a function of the phase of the menstrual cycle, no significant difference in sFRP1 mRNA levels could be detected, whereas levels of Wnt5b transcript were significantly higher in the secretory phase in myometrial cells. Treatment with 9-cis retinoic acid significantly inhibited Wnt5b expression in myometrial SMC but not in their leiomyoma counterparts.

Conclusions: Specific Wnt signaling genes are overexpressed in leiomyoma cells. Moreover, in these cells, the regulation of Wnt5b expression by retinoids appears to be attenuated.

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