Estrogens promote invasion of prostate cancer cells in a paracrine manner through up-regulation of matrix metalloproteinase 2 in prostatic stromal cells.
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 (E(2)) treatment up-regulates MMP2 production in PrSC, which promotes PCa cell invasion in a paracrine manner. Conditioned medium (CM) was collected from E(2)-treated prostatic stromal cell line WPMY-1 and primary PrSC. The CM of E(2)-treated WPMY-1 and PrSC promoted invasion of PCa cells, as measured by Matrigel transwell assays. Treatment with E(2) 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 E(2)-induced MMP2 expression in WPMY-1 cells. Mechanistic studies showed that E(2) up-regulated MMP2 in an indirect manner: E(2) induced TGFβ1 expression via ERα; TGFβ1 stimulated MMP2 expression in PrSC; the invasion of PCa cells were stimulated by elevated MMP2 expression induced by E(2) in a paracrine manner. Our data show that E(2) induces MMP2 expression in WPMY-1 and PrSC cells, which was mediated by TGFβ1. The effect of E(2) on invasion of PCa cells is mediated by up-regulation of MMP2 in a paracrine mechanism.
Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of Ministry of Education, Nankai University, Tianjin 300071, China.
Lin
L
Yu
Chun-Yu
CY
Wang
Jiandang
J
Shi
Lin
L
Miao
Xiaoling
X
Du
Doris
D
Mayer
Ju
J
Zhang
D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D000077267:Fulvestrant; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019899:Paracrine Communication / Q000502:physiology*; D011467:Prostate / Q000166:cytology*; D011471:Prostatic Neoplasms / Q000378:metabolism; D011959:Receptors, Estradiol / Q000037:antagonists & inhibitors; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D017077:Culture Media, Conditioned; D011959:Receptors, Estradiol; D053773:Transforming Growth Factor beta1; D000077267:Fulvestrant; D004958:Estradiol; D020778:Matrix Metalloproteinase 2