Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, PR China.
PLoS One. 2013 May 29;8(5):e65906. doi: 10.1371/journal.pone.0065906. Print 2013.
TGF-β1 has the potential to activate multiple signaling pathways required for inducing metastatic potential of tumor cells. However, TGF-β1 was inefficient in inducing metastatic potential of many non-invasive human tumor cells. Here we report that the enhancement of TGF-β1 signaling is required for inducing metastatic potential of non-invasive breast cancer cells. TGF-β1 alone could not efficiently induce the sustained activation of Smad and non-Smad pathways in non-invasive breast cancer cells. TLR4 ligand (LPS) and H₂O₂ cooperated with TGF-β1 to enhance the sustained activation of non-Smad pathways, including p38MAPK, ERK, JNK, PI3K, and NF-κB. The activation of MAPK and PI3K pathways resulted in a positive feed-back effect on TGF-β1 signaling by down-regulating Nm23-H1 expression and up-regulating the expression of TβRI and TβRII, favoring further activation of multiple signaling pathways. Moreover, the enhanced TGF-β1 signaling induced higher expression of SNAI2, which also promoted TβRII expression. Therefore, the sustained activation levels of both Smad and non-Smad pathways were gradually increased after prolonged stimulation with TGF-β1/H₂O₂/LPS. Consistent with the activation pattern of signaling pathways, the invasive capacity and anoikis-resistance of non-invasive breast cancer cells were gradually increased after prolonged stimulation with TGF-β1/H₂O₂/LPS. The metastatic potential induced by TGF-β1/H₂O₂/LPS was sufficient for tumor cells to extravasate and form metastatic foci in an experimental metastasis model in nude mice. The findings in this study suggested that the enhanced signaling is required for inducing higher metastatic capacity of tumor cells, and that targeting one of stimuli or signaling pathways might be potential approach in comprehensive strategy for tumor therapy.
TGF-β1 具有激活多种信号通路的潜力，这些信号通路对于诱导肿瘤细胞的转移潜能是必需的。然而，TGF-β1 并不能有效地诱导许多非侵袭性人肿瘤细胞的转移潜能。在这里，我们报告 TGF-β1 信号的增强对于诱导非侵袭性乳腺癌细胞的转移潜能是必需的。TGF-β1 本身不能有效地诱导非侵袭性乳腺癌细胞中非 Smad 信号通路的持续激活。TLR4 配体（LPS）和 H₂O₂ 与 TGF-β1 协同作用，增强非 Smad 信号通路的持续激活，包括 p38MAPK、ERK、JNK、PI3K 和 NF-κB。MAPK 和 PI3K 通路的激活通过下调 Nm23-H1 表达和上调 TβRI 和 TβRII 的表达，对 TGF-β1 信号产生正反馈效应，有利于进一步激活多种信号通路。此外，增强的 TGF-β1 信号诱导 SNAI2 的更高表达，这也促进了 TβRII 的表达。因此，在 TGF-β1/H₂O₂/LPS 的长期刺激下，Smad 和非 Smad 信号通路的持续激活水平逐渐增加。与信号通路的激活模式一致，在 TGF-β1/H₂O₂/LPS 的长期刺激下，非侵袭性乳腺癌细胞的侵袭能力和失巢凋亡抗性逐渐增加。TGF-β1/H₂O₂/LPS 诱导的转移潜能足以使肿瘤细胞在裸鼠实验性转移模型中逸出并形成转移灶。本研究的结果表明，增强的信号对于诱导肿瘤细胞更高的转移能力是必需的，而针对一种刺激或信号通路可能是肿瘤综合治疗策略中的一种潜在方法。
