Retinoid orphan nuclear receptor alpha (RORα) suppresses the epithelial-mesenchymal transition (EMT) by directly repressing Snail transcription.
Retinoid orphan nuclear receptor alpha (RORα) suppresses the epithelial-mesenchymal transition (EMT) by directly repressing Snail transcription.
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维甲酸孤儿核受体α（RORα）通过直接抑制Snail转录来抑制上皮-间质转化（EMT）。
DOI：
10.1016/j.jbc.2022.102059
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发表时间：
2022-07
影响因子：
4.8
通讯作者：
Xu, Ren
中科院分区：
文献类型：
--
作者：
Xiong, Gaofeng;Xu, Ren
视黄醇孤儿核受体α(RoRα)是孤儿核因子家族的一员，通过与RoR反应元件(RORE)结合来调节基因表达。RoRα已被确定为一种潜在的肿瘤抑制因子；然而，下调RoRα如何促进癌症进展尚不完全清楚。在此，我们发现在蜗牛、螺旋或转化生长因子-α诱导的上皮-间充质转化过程中，RoR-β的蛋白水平下调。我们发现，沉默RoRα诱导MCF10A细胞中间充质标志物的表达，伴随着细胞侵袭、迁移和乳房形成的增强。此外，异位表达RoRα可抑制转化生长因子-β诱导的MCF10A和HMLE细胞内胚层转化过程。这些结果表明，RoRα的下调在诱导乳腺上皮细胞上皮细胞转化过程中起着至关重要的作用。通过分析对照细胞和RoRα表达细胞的基因表达谱，我们还确定了一个关键的EMT调控因子Snail，它是RoRα的潜在靶点。我们发现，RoRα的表达显著抑制了乳腺癌细胞中Snail的转录。染色质免疫沉淀分析表明，RoRα与SNAI1基因启动子区域的RORE结合，利用荧光素酶报告基因分析，我们发现RoRα与RORE的结合是抑制钉螺转录的关键。最后，救援实验证实，Snail介导了RoRα功能，抑制了EMT和乳房大气层的形成。这些结果揭示了RoRα在抑制内膜转移中的新功能，并确认Snail是乳腺上皮细胞中RoRα的直接靶点。
Retinoid orphan nuclear receptor alpha (RORα) is a member of the orphan nuclear factor family and regulates gene expression by binding to ROR response elements (ROREs). RORα has been identified as a potential tumor suppressor; however, how downregulation of RORα promotes cancer progression is not fully understood. Here, we showed that protein levels of RORα were downregulated during the Snail-, Twist-, or transforming growth factor-β–induced epithelial–mesenchymal transition (EMT). We found that silencing of RORα induced expression of mesenchymal markers in MCF10A cells, accompanied by enhanced cell invasion, migration, and mammosphere formation. Furthermore, ectopic expression of RORα suppressed transforming growth factor-β–induced EMT processes in MCF10A and HMLE cells. These results indicate that downregulation of RORα is crucial for the induction of EMT in mammary epithelial cells. By analyzing gene expression profiles in control and RORα-expressing cells, we also identified Snail, a key regulator of EMT, as a potential target of RORα. We show that RORα expression significantly inhibits Snail transcription in breast cancer cells. Chromatin immunoprecipitation analysis demonstrated that RORα bound to the ROREs in promoter region of SNAI1 gene, and using the luciferase reporter assay, we showed that binding to the ROREs was critical for RORα to repress Snail transcription. Finally, rescue experiments substantiated that Snail mediates RORα function in suppressing EMT and mammosphere formation. These results reveal a novel function of RORα in suppressing EMT and identify Snail as a direct target of RORα in mammary epithelial cells.
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影响因子：
11.2
作者：
Charafe-Jauffret E;Ginestier C;Iovino F;Wicinski J;Cervera N;Finetti P;Hur MH;Diebel ME;Monville F;Dutcher J;Brown M;Viens P;Xerri L;Bertucci F;Stassi G;Dontu G;Birnbaum D;Wicha MS
通讯作者：
Wicha MS
DOI：
10.1621/nrs.07003
发表时间：
2009
期刊：
Nuclear receptor signaling
影响因子：
--
作者：
Jetten AM
通讯作者：
Jetten AM
影响因子：
5.3
作者：
Carver, EA;Jiang, RL;Gridley, T
通讯作者：
Gridley, T
视黄酸受体相关受体α（RORα）是肝细胞癌的预后标志物
影响因子：
--
作者：
Fu, Rong-Dang;Qiu, Chun-Hui;Lu, Min-Qiang
通讯作者：
Lu, Min-Qiang
雌激素受体沉默可诱导人乳腺癌细胞上皮细胞向间质细胞的转变。
影响因子：
3.7
作者：
Al Saleh S;Al Mulla F;Luqmani YA
通讯作者：
Luqmani YA