Androgen receptor and microRNA-21 axis downregulates transforming growth factor beta receptor II (TGFBR2) expression in prostate cancer.
Androgen receptor and microRNA-21 axis downregulates transforming growth factor beta receptor II (TGFBR2) expression in prostate cancer.
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前列腺癌细胞通过下调tgf - β受体来逃避tgf - β的生长抑制。然而，癌细胞下调前列腺TGFβ受体的机制尚不清楚。在这里，我们发现miR-21和雄激素受体（AR）信号的协同作用在抑制前列腺癌细胞中TGFβ受体II （TGFBR2）的表达中发挥了关键作用。我们的研究结果表明，miR-21通过结合其3'UTR和AR信号抑制TGFBR2水平，进一步增强了未转化和转化的人类前列腺上皮细胞以及人类前列腺癌中的这种作用。对原发性前列腺癌的分析显示，miR-21/AR表达的增加与TGFBR2表达的显著降低并行。在未转化和转化的人前列腺上皮细胞、人前列腺癌异种移植物和小鼠前列腺中，操纵雄激素信号或AR或miR-21的表达水平会改变TGFBR2的表达。重要的是，我们证明了miR-21和AR相互调节表达，形成一个正反馈回路。我们的研究结果表明，miR-21/AR通过减弱tgf β介导的Smad2/3激活、细胞生长抑制、细胞迁移和细胞凋亡来调节其促瘤功能。综上所述，这些结果表明AR和miR-21轴通过下调TGFBR2在前列腺肿瘤中发挥其致癌作用，从而抑制TGFβ通路的肿瘤抑制活性。单独靶向miR-21或联合AR可恢复TGFβ在前列腺癌中的抑瘤活性。
Prostate cancer cells escape growth inhibition from TGFβ by down-regulating TGFβ receptors. However, the mechanism by which cancer cells down-regulate TGFβ receptors in prostate is not clear. Here, we showed that coordinated action of miR-21 and androgen receptor (AR) signaling played a critical role in inhibiting TGFβ receptor II (TGFBR2) expression in prostate cancer cells. Our results revealed that miR-21 suppresses TGFBR2 levels by binding to its 3'UTR and AR signaling further potentiates this effect in both untransformed and transformed human prostate epithelial cells as well as in human prostate cancers. Analysis of primary prostate cancers showed that increased miR-21/AR expression parallel a significantly reduced expression of TGFBR2. Manipulation of androgen signaling or the expression levels of AR or miR-21 negatively altered TGFBR2 expression in untransformed and transformed human prostate epithelial cells, human prostate cancer xenografts, and mouse prostate glands. Importantly, we demonstrated that miR-21 and AR regulated each other's expression resulting in a positive feedback loop. Our results indicated that miR-21/AR mediate its tumor promoting function by attenuating TGFβ-mediated Smad2/3 activation, cell growth inhibition, cell migration, and apoptosis. Together, these results suggest that the AR and miR-21 axis exerts its oncogenic effects in prostate tumors by down-regulating TGFBR2, hence inhibiting the tumor suppressive activity of TGFβ pathway. Targeting miR-21 alone or in combination with AR may restore the tumor inhibitory activity of TGFβ in prostate cancer.
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