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首页> 外文期刊>Oncogene >17beta-Estradiol upregulates and activates WOX1/WWOXv1 and WOX2/WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo.
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17beta-Estradiol upregulates and activates WOX1/WWOXv1 and WOX2/WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo.

机译：17β-雌二醇在体外上调和激活 WOX1/WWOXv1 和 WOX2/WWOXv2：在体内乳腺癌和前列腺癌变进展至转移前状态中的潜在作用。

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Human WWOX gene encodes a proapoptotic WW domain-containing oxidoreductase WOX1 (also named WWOX, FOR2 or WWOXv1). Apoptotic and stress stimuli activate WOX1 via Tyr33 phosphorylation and nuclear translocation. WOX1 possesses a tetrad NSYK motif in the C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, which may bind estrogen and androgen. Here, we determined that 17beta-estradiol (E(2)) activated WOX1, p53 and ERK in COS7 fibroblasts, primary lung epithelial cells, and androgen receptor (AR)-negative prostate DU145 cells, but not in estrogen receptor (ER)-positive breast MCF7 cells. Androgen also activated WOX1 in the AR-negative DU145 cells. These observations suggest that sex hormone-mediated Tyr33 phosphorylation and nuclear translocation of WOX1 is independent of ER and AR. Stress stimuli increase physical binding of p53 with WOX1 in vivo. We determined here that E(2) increased the formation of p53/WOX1 complex and their nuclear translocation in COS7 cells; however, nuclear translocation of this complex could not occur in MCF7 cells. By immunohistochemistry, we determined that progression of prostate from normal to hyperplasia, cancerous and metastatic stages positively correlate with upregulation and activation of WOX1 and WOX2 (FOR1/WWOXv2). In contrast, breast cancer development to a premetastatic state is associated with upregulation and Tyr33 phosphorylation of cytosolic WOX1 and WOX2, followed by significant downregulation or absent expression during metastasis. These Tyr33-phosphorylated proteins are mostly located in the mitochondria without translocating to the nuclei, which is comparable to those findings in cultured breast cancer cells. Together, sex steroid hormone-induced activation of WOX1 and WOX2 is independent of ER and AR, and this activation positively correlates with cancerous progression of prostate and breast to a premetastatic state.
机译：人 WWOX 基因编码含有促凋亡 WW 结构域的氧化还原酶 WOX1（也称为 WWOX、FOR2 或 WWOXv1）。细胞凋亡和应激刺激通过 Tyr33 磷酸化和核易位激活 WOX1。WOX1 在 C 端短链醇脱氢酶/还原酶 （SDR） 结构域中具有四联 NSYK 基序，可结合雌激素和雄激素。在这里，我们确定 17β-雌二醇 （E（2）） 激活 COS7 成纤维细胞、原代肺上皮细胞和雄激素受体 （AR） 阴性前列腺 DU145 细胞中的 WOX1、p53 和 ERK，但不激活雌激素受体 （ER） 阳性乳腺 MCF7 细胞。雄激素还激活了 AR 阴性 DU145 细胞中的 WOX1。这些观察结果表明，性激素介导的 WOX1 的 Tyr33 磷酸化和核易位与 ER 和 AR 无关。我们在这里确定 E（2） 增加了 p53/WOX1 复合物的形成及其在 COS7 细胞中的核易位;然而，该复合物的核易位不会发生在 MCF7 细胞中。通过免疫组化，我们确定前列腺从正常到增生、癌变和转移阶段的进展与 WOX1 和 WOX2 （FOR1/WWOXv2） 的上调和激活呈正相关。相反，乳腺癌发展到转移前状态与胞质 WOX1 和 WOX2 的上调和 Tyr33 磷酸化有关，随后在转移期间显着下调或缺失表达。这些 Tyr33 磷酸化蛋白大多位于线粒体中，没有易位到细胞核，这与培养的乳腺癌细胞中的发现相当。总之，性类固醇激素诱导的 WOX1 和 WOX2 激活与 ER 和 AR 无关，这种激活与前列腺和乳房癌变进展为转移前状态呈正相关。

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