Modulation of NFκB activity and e-cadherin by the type III transforming growth factor ß receptor regulates cell growth and motility
Modulation of NFκB activity and e-cadherin by the type III transforming growth factor ß receptor regulates cell growth and motility
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DOI：
10.1074/jbc.m704434200
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发表时间：
2007-11-02
影响因子：
4.8
通讯作者：
Arteaga, Carlos L.
中科院分区：
文献类型：
--
作者：
Criswell, Tracy L.;Arteaga, Carlos L.
转化生长因子β在非转化上皮细胞中是生长抑制性的，但在肿瘤发生期间变成生长促进性的。I型和II型受体在肿瘤发生中的作用已被广泛研究，但普遍表达的III型受体（T β RIII）的作用仍然难以捉摸。我们开发了针对T β RIII的短发夹RNA，以研究该受体在乳腺癌肿瘤发生中的作用。稳定表达小鼠T β RIII特异性短发夹RNA（NM-kd）的非致瘤性NMuMG小鼠细胞与表达人T β RIII特异性短发夹RNA（NM-con）的对照细胞相比，表现出细胞生长、运动性和侵袭性增加。用大鼠T β RIII重建T β RIII表达消除了NM-kd细胞中观察到的生长和运动性增加。此外，NM-kd细胞的粘附连接蛋白E-cadherin的表达明显减少。这种E-钙粘蛋白的丢失是由于NF κ B B活性的增加，这反过来又导致E-钙粘蛋白的转录抑制因子如Snail、Slug、Twist和Sip 1的表达增加。最后，T β RIII被敲低的NMuMG细胞在无胸腺裸鼠中形成了侵袭性肿瘤，而对照细胞则没有。这些数据表明，T β RIII在非致瘤性乳腺上皮细胞中至少部分通过抑制NF κ B介导的E-钙粘蛋白抑制而发挥肿瘤抑制作用。
Transforming growth factor beta is growth-inhibitory in non-transformed epithelial cells but becomes growth-promoting during tumorigenesis. The role of the type I and II receptors in tumorigenesis has been extensively studied, but the role of the ubiquitously expressed type III receptor (T beta RIII) remains elusive. We developed short hairpin RNAs directed against T beta RIII to investigate the role of this receptor in breast cancer tumorigenesis. Nontumorigenic NMuMG mouse cells stably expressing short hairpin RNA specific to mouse T beta RIII (NM-kd) demonstrated increased cell growth, motility, and invasion as compared with control cells expressing shRNA to human T beta RIII (NM-con). Reconstitution of T beta RIII expression with rat T beta RIII abrogated the increased growth and motility seen in the NM-kd cells. In addition, the NM-kd cells exhibited marked reduction in the expression of the adherens junction protein, E-cadherin. This loss of E-cadherin was due to increased NF kappa B activity that, in turn, resulted in increased expression of the transcriptional repressors of E-cadherin such as Snail, Slug, Twist, and Sip1. Finally, NMuMG cells in which T beta RIII had been knocked down formed invasive tumors in athymic nude mice, whereas the control cells did not. These data indicate that T beta RIII acts as a tumor suppressor in nontumorigenic mammary epithelial cells at least in part by inhibiting NF kappa B-mediated repression of E-cadherin.