Erb-041, an estrogen receptor-β agonist, inhibits skin photocarcinogenesis in SKH-1 hairless mice by downregulating the WNT signaling pathway.
Erb-041, an estrogen receptor-β agonist, inhibits skin photocarcinogenesis in SKH-1 hairless mice by downregulating the WNT signaling pathway.
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DOI：
10.1158/1940-6207.capr-13-0276
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发表时间：
2014-02
期刊：
影响因子：
--
通讯作者：
Athar M
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文献类型：
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作者：
Chaudhary SC;Singh T;Talwelkar SS;Srivastava RK;Arumugam A;Weng Z;Elmets CA;Afaq F;Kopelovich L;Athar M
雌激素受体（ER）包括ERα和ERβ，在多种细胞类型中调节多种生物学反应。ERβ的表达在多种癌症中丢失。ERβ-激动剂显示调节炎症、癌细胞增殖和分化。在这里，我们研究了Erb-041的癌症化学预防特性，Erb-041是一种ERβ激动剂，采用UVB诱导的SKH-1小鼠光致癌模型。Erb-041显著降低UVB诱导的致癌作用。与UVB（单独）对照相比，Erb-041处理组的肿瘤数量和体积分别减少60%和84%。这种抑制肿瘤发生伴随着减少PCNA，细胞周期蛋白D1，VEGF和CD 31;和增加细胞凋亡。Erb-041治疗显著恢复SCC中ERβ表达的丢失。此外，UVB诱导的炎症反应显着减少。髓过氧化物酶活性;细胞因子IL 1 β、IL 6和IL 10水平以及p-ERK 1/2、p-p38、p-IκB、iNOS、考克斯-2和核NFκ Bp 65表达降低。肿瘤相关炎性细胞（GR-1+/CD 11b+和F4/80+）的数量也减少。从Erb-041治疗的动物切除的肿瘤侵袭性较小，并且显示上皮-间质转化（EMT）减少。E-cadherin表达增强，N-cadherin、Snail、Slug和Twist表达减少。发现作为皮肤癌发病机制基础的WNT/β-连环蛋白信号传导途径被Erb-041治疗下调。在用WNT信号传导抑制剂XAV 939处理肿瘤细胞后，观察到增殖和EMT调节蛋白的相似但不相同的变化。我们的研究结果表明，Erb-041是一种有效的皮肤癌化学预防剂，其通过抑制WNT/β-catenin信号通路起作用。
Estrogen receptors (ERs) including ERα and ERβ are known to regulate multiple biological responses in various cell-types. The expression of ERβ is lost in various cancers. ERβ-agonists were shown to modulate inflammation, cancer cell proliferation and differentiation. Here, we investigated the cancer chemopreventive properties of Erb-041, an ERβ agonist employing a model of UVB-induced photocarcinogenesis in SKH-1 mice. Erb-041 significantly reduced UVB-induced carcinogenesis. Tumor numbers and volume were reduced by 60% and 84%, respectively in Erb-041-treated group as compared to UVB (alone) control. This inhibition in tumorigenesis was accompanied by the decrease in PCNA, cyclin D1, VEGF and CD31; and increase in apoptosis. The lost ERβ expression in SCCs was significantly recovered by Erb-041 treatment. Additionally, the UVB-induced inflammatory responses were remarkably reduced. Myeloperoxidase activity; levels of cytokines IL1β, IL6 and IL10; and expression of p-ERK1/2, p-p38, p-IκB, iNOS, COX-2 and nuclear NFκBp65 were diminished. The number of tumor-associated inflammatory cells (GR-1+/CD11b+ and F4/80+) was also decreased. Tumors excised from Erb-041-treated animal were less invasive and showed reduced epithelial-mesenchymal transition (EMT). The enhanced expression of E-cadherin with the concomitantly reduced expression of N-Cadherin, Snail, Slug and Twist characterized these lesions. WNT/β-catenin signaling pathway, which underlies pathogenesis of skin cancer was found to be down-regulated by Erb-041 treatment. Similar but not identical changes in proliferation and EMT regulatory proteins were noticed following treatment of tumor cells with a WNT-signaling inhibitor XAV939. Our results show that Erb-041 is a potent skin cancer chemopreventive agent which acts by dampening WNT/β-catenin signaling pathway.