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

机译：17 |β|-雌二醇在体外上调并激活WOX1 | [sol] | WWOXv1和WOX2 | [sol] | WWOXv2：体内乳腺癌和前列腺癌转移至转移前状态的潜在作用

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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 17-estradiol (E2) 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 E2 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基因编码含有凋亡的WW域的氧化还原酶WOX1（也称为WWOX，FOR2或WWOXv1）。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）域中具有一个四联体NSYK基序，它可以结合雌激素和雄激素。在这里，我们确定17-雌二醇（E2）激活了COS7成纤维细胞，原代肺上皮细胞和雄激素受体（AR）阴性的前列腺DU145细胞中的WOX1，p53和ERK，但未激活雌激素受体（ER）阳性的乳腺癌MCF7细胞。雄激素还激活AR阴性DU145细胞中的WOX1。这些观察结果表明，性激素介导的Tyr33磷酸化和WOX1的核易位独立于ER和AR。体内应激刺激增加p53与WOX1的物理结合。我们在这里确定E2增加了p53 / WOX1复合物的形成及其在COS7细胞中的核易位。但是，这种复合物的核转位不能在MCF7细胞中发生。通过免疫组织化学，我们确定前列腺从正常发展到增生，癌变和转移阶段与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浆WOX1和WOX2的上调和Tyr33磷酸化有关，随后在转移过程中明显下调或表达缺失。这些Tyr33磷酸化的蛋白质大部分位于线粒体中，而不会移位到细胞核，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，并且这种激活与前列腺癌和乳腺癌向转移前状态的癌变正相关。

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