The tumor suppressor Smad4 is required for transforming growth factor β-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells
The tumor suppressor Smad4 is required for transforming growth factor β-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells
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DOI：
10.1158/0008-5472.can-05-3560
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发表时间：
2006-02-15
期刊：
影响因子：
11.2
通讯作者：
ten Dijke, P
中科院分区：
文献类型：
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作者：
Deckers, M;van Dinther, M;ten Dijke, P
转化生长因子β（TGF-β）可以作为癌症进展的抑制剂和促进剂。细胞内 Smad 蛋白（即受体调节的 Smad 和常见介质 Smad4）在介导 TGF-β 的抗有丝分裂和促凋亡作用中发挥关键作用，但它们在 TGF-β 诱导的侵袭和转移中的功能尚不清楚。在这里，我们研究了 Smad4 在 TGF-β 诱导的乳腺癌进展的细胞和小鼠模型中的作用。与其肿瘤抑制功能一致，使用表达小发夹 RNA (shRNA) 的 RNAi 载体对 NMuMG 乳腺上皮细胞中的 Smad4 进行特异性沉默，可显着减轻 TGF-β 诱导的生长抑制和细胞凋亡。 Smad4 敲低还有效抑制 TGF-β 诱导的 NMuMG 细胞上皮向间质转化，通过从上皮细胞向成纤维细胞样细胞的形态转变、应激纤维的形成、E-钙粘蛋白表达的抑制以及各种间质标记物表达的增加来测量。此外，我们发现在 MDA-MB-231 乳腺癌细胞中敲低 Smad4 可强烈抑制裸鼠骨转移频率达 75%，并显着提高无转移生存率。 MDA-MB-231 细胞与骨微环境的通讯是最佳肿瘤细胞生长和转移所必需的，但在 Smad4 敲低细胞中可能会受到影响，因为 TGF-β 诱导的白细胞介素 11 表达在 Smad4 敲低后减弱。综上所述，我们的结果表明 Smad4 在肿瘤抑制和乳腺癌细胞进展中发挥着重要作用。
Transforming growth factor beta (TGF-beta) can act as suppressor and promoter of cancer progression. Intracellular Smad proteins (i.e., receptor regulated Smads and common mediator Smad4) play a pivotal role in mediating antimitogenic and proapoptotic effects of TGF-beta, but their function in TGF beta-induced invasion and metastasis is unclear. Here, we have investigated the role of Smad4 in a cellular and mouse model for TGF-beta-induced breast cancer progression. Consistent with its tumor suppressor function, specific silencing of Smad4 in NMuMG mammary gland epithelial cells using small hairpin RNA (shRNA)-expressing RNAi vectors strongly mitigated TGF-beta-induced growth inhibition and apoptosis. Smad4 knockdown also potently inhibited TGF-beta-induced epithelial to mesenchymal transition of NMuMG cells as measured by morphologic transformation from epithelial to fibroblast-like cells, formation of stress fibers, inhibition of E-cadherin expression, and gain of expression of various mesenchymal markers. Furthermore, we show that knockdown of Smad4 in MDA-MB-231 breast cancer cells strongly inhibited the frequency of bone metastasis in nude mice by 75% and significantly increased metastasis-free survival. Communication of MDA-MB-231 cells with the bone microenvironment, which is needed for optimal tumor cell growth and metastasis, may be affected in Smad4 knockdown cells as TGF-beta-induced expression of interleukin 11 was attenuated on Smad4 knockdown. Taken together, our results show that Smad4 plays an important role in both tumor suppression and progression of breast cancer cells.