Differential regulatory effect of progesterone on the proliferation and apoptosis of uterine leiomyoma tissue explants and primary leiomyoma cell cultures

Abstract

Objective: The growth of uterine leiomyomas is regulated by progesterone, although the underlying molecular mechanisms are not fully understood.Methods: Primary leiomyoma cells were isolated by standard method from 16 samples of uterine leiomyoma tissue. Uterine leiomyoma explants and primary leiomyoma cell cultures were exposed to progesterone in concentrations of 0.01 μg/ml, 0.1 μg/ml and 1 μg/ ml for 24 h. Cell apoptosis was assessed with Annexin V assays performed in cell cultures by flow cytometry. The expression of PR-A, PR-B, Ki67, Akt, ERK, PTEN and PPARγ mRNAs was estimated in cultured leiomyoma cells and tissue explants by real time RT-PCR.Results: Treatment with progesterone promoted viability and proliferation of cultured leiomyoma cells in a dose-dependent manner. Low and high doses of progesterone decreased early apoptosis of leiomyoma cells. High concentrations of progesterone increased the number of living cells in Annexin V assays. High doses of progesterone increased the expression of Ki67 mRNA, while low doses increased the expression of PR-A mRNA in cultured leiomyoma cells and tissue explants. In cell cultures, low doses of progesterone increased the expression of PR-B mRNA and the expression of PTEN and PPARγ mRNAs in a dose-dependent manner. Exposure of leiomyoma tissue explants to progesterone led to increased expression of PR-B and ERK mRNAs in a dose-dependent manner.Conclusions: The effects of progesterone on the apoptosis and proliferation of leiomyoma cells was dosedependent and different in cell cultures and leiomyoma explants, possibly as a result of impacts derived from the tumor microenvironment.

A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity

“…Increased proliferative activity has also been observed in ULs of postmenopausal women following combined oestrogen and progesterone therapy in comparison to those with oestrogen therapy or without hormone replacement [ 45 , 49 ]. Progesterone-mediated UL growth regulation does not only occur through increased proliferation but also through decreased apoptosis and higher ECM accumulation [ 46 , 50 , 51 ]. Directly or via interacting with other transcription factors, progesterone receptors can regulate the expression of many genes, in particular, proliferating cell nuclear antigen (PCNA), epidermal growth factor (EGF), transforming growth factor beta (TGF-β), anti-apoptotic Bcl-2 protein and the miR-29b microRNA, which regulates the accumulation of ECM [ 37 , 52 ].…”