Division of Molecular and Genomic Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan.
Biochem J. 2010 Feb 24;426(3):327-35. doi: 10.1042/BJ20090990.
TGF-beta (transforming growth factor-beta) induces a cytostatic response in most normal cell types. In cancer cells, however, it often promotes metastasis, and its high expression is correlated with poor prognosis. In the present study, we show that S100A4, a metastasis-associated protein, also called metastatin-1, can physically and functionally interact with Smad3, an important mediator of TGF-beta signalling. In agreement with its known property, S100A4 binds to Smad3 in a Ca2+-dependent manner. The S100A4-binding site is located in the N-terminal region of Smad3. S100A4 can potentiate transcriptional activity of Smad3 and the related Smad2. When exogenously expressed in MCF10CA1a.cl1, an MCF10-derived breast cancer cell line, S100A4 increases TGF-beta-induced MMP-9 (matrix metalloproteinase-9) expression. On the other hand, depletion of S100A4 by siRNA (small interfering RNA) from the MDA-MB231 cell line results in attenuation of MMP-9 induction by TGF-beta. Consistent with these observations, S100A4 increases cell invasion ability induced by TGF-beta in MCF10CA1a.cl1 cells, and depletion of the protein in MDA-MB-231 cells inhibits it. Because expression of both S100A4 and TGF-beta is highly elevated in many types of malignant tumours, S100A4 and Smad3 may co-operatively increase metastatic activity of some types of cancer cells.
TGF-β（转化生长因子-β）可诱导大多数正常细胞类型产生细胞静止反应。然而，在癌细胞中，它通常促进转移，其高表达与预后不良相关。在本研究中，我们表明，S100A4，一种与转移相关的蛋白，也称为 metastatin-1，可以与 Smad3 物理和功能相互作用，Smad3 是 TGF-β信号转导的重要介质。与已知的特性一致，S100A4 以 Ca2+依赖的方式与 Smad3 结合。S100A4 的结合位点位于 Smad3 的 N 端区域。S100A4 可以增强 Smad3 和相关 Smad2 的转录活性。当在 MCF10CA1a.cl1（一种源自 MCF10 的乳腺癌细胞系）中体外表达时，S100A4 增加 TGF-β诱导的 MMP-9（基质金属蛋白酶-9）表达。另一方面，通过 siRNA（小干扰 RNA）从 MDA-MB231 细胞系中耗尽 S100A4 会导致 TGF-β诱导的 MMP-9 诱导减弱。与这些观察结果一致，S100A4 增加 TGF-β在 MCF10CA1a.cl1 细胞中诱导的细胞侵袭能力，并且在 MDA-MB-231 细胞中耗尽该蛋白会抑制侵袭能力。由于 S100A4 和 TGF-β的表达在许多类型的恶性肿瘤中都高度升高，因此 S100A4 和 Smad3 可能协同增加某些类型癌细胞的转移活性。
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