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Lin Yu, Chun-Yu Wang, Jiandang Shi, Lin Miao, Xiaoling Du, Doris Mayer, Ju Zhang, Estrogens Promote Invasion of Prostate Cancer Cells in a Paracrine Manner through Up-Regulation of Matrix Metalloproteinase 2 in Prostatic Stromal Cells, Endocrinology, Volume 152, Issue 3, 1 March 2011, Pages 773–781, https://doi.org/10.1210/en.2010-1239
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Accumulating evidence suggests an enhancing effect of estrogens on prostate cancer (PCa) progression. Matrix metalloproteinase 2 (MMP2), which plays an important role in prostate cancer invasion, is mainly expressed in prostatic stromal cells (PrSC). Here we show that estradiol (E2) treatment up-regulates MMP2 production in PrSC, which promotes PCa cell invasion in a paracrine manner. Conditioned medium (CM) was collected from E2-treated prostatic stromal cell line WPMY-1 and primary PrSC. The CM of E2-treated WPMY-1 and PrSC promoted invasion of PCa cells, as measured by Matrigel transwell assays. Treatment with E2 and 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, an estrogen receptor-alpha (ERα) specific agonist, significantly up-regulated MMP2 expression in WPMY-1 and PrSC cells at both mRNA and protein levels. The CM treated with an anti-MMP2 antibody lost the stimulatory effect on invasion of PCa cells. The ER inhibitor ICI 182,780, as well as a TGFβ1 neutralizing antibody and ERα-specific small interfering RNA effectively suppressed E2-induced MMP2 expression in WPMY-1 cells. Mechanistic studies showed that E2 up-regulated MMP2 in an indirect manner: E2 induced TGFβ1 expression via ERα; TGFβ1 stimulated MMP2 expression in PrSC; the invasion of PCa cells were stimulated by elevated MMP2 expression induced by E2 in a paracrine manner. Our data show that E2 induces MMP2 expression in WPMY-1 and PrSC cells, which was mediated by TGFβ1. The effect of E2 on invasion of PCa cells is mediated by up-regulation of MMP2 in a paracrine mechanism.
