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Estrogens promote invasion of prostate cancer cells in a paracrine manner through up-regulation of matrix metalloproteinase 2 in prostatic stromal cells.

机译:雌激素通过上调前列腺基质细胞中基质金属蛋白酶2的分泌来促进前列腺癌细胞的侵袭。

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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 (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 (ERalpha) 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 TGFbeta1 neutralizing antibody and ERalpha-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 TGFbeta1 expression via ERalpha; TGFbeta1 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 TGFbeta1. The effect of E(2) on invasion of PCa cells is mediated by up-regulation of MMP2 in a paracrine mechanism.
机译:越来越多的证据表明,雌激素对前列腺癌(PCa)进展具有增强作用。在前列腺癌侵袭中起重要作用的基质金属蛋白酶2(MMP2)主要在前列腺基质细胞(PrSC)中表达。在这里,我们显示雌二醇(E(2))处理可上调PrSC中的MMP2生成,从而以旁分泌的方式促进PCa细胞的侵袭。从E(2)处理的前列腺基质细胞系WPMY-1和原发性PrSC收集条件培养基(CM)。 E(2)处理的WPMY-1和PrSC的CM促进了PCa细胞的侵袭,如通过Matrigel Transwell分析所测量的。用E(2)和1,3,5-Tris(4-羟苯基)-4-丙基-1H-吡唑(一种雌激素受体α(ERalpha)特异性激动剂)处理,可明显上调WPMY-1和MMP2的表达。在mRNA和蛋白质水平上的PrSC细胞。用抗MMP2抗体处理的CM失去了对PCa细胞侵袭的刺激作用。 ER抑制剂ICI 182,780以及TGFbeta1中和抗体和ERalpha特异性小干扰RNA有效抑制WPMY-1细胞中E(2)诱导的MMP2表达。机理研究表明,E(2)以间接方式上调MMP2:E(2)通过ERalpha诱导TGFbeta1表达; E(2)通过ERalpha诱导TGFbeta1表达。 TGFbeta1刺激PrSC中的MMP2表达; E(2)诱导的MMP2表达升高以旁分泌方式刺激PCa细胞的侵袭。我们的数据表明E(2)诱导WPMY-1和PrSC细胞中的MMP2表达,这是由TGFbeta1介导的。 E(2)对PCa细胞侵袭的影响是由旁分泌机制中MMP2的上调介导的。

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