Liao Sheng-Jun, Luo Jing, Li Dong, Zhou Yuan-Hong, Yan Bin, Wei Jing-Jing, Tu Jian-Cheng, Li Yi-Rong, Zhang Gui-Mei, Feng Zuo-Hua
Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, People's Republic of China.
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, Hubei, People's Republic of China.
J Cell Commun Signal. 2019 Sep;13(3):369-380. doi: 10.1007/s12079-019-00508-8. Epub 2019 Feb 9.
TGF-β1 is a main inducer of epithelial to mesenchymal transition (EMT). However, many breast cancer cells are not sensitive to the EMT induction by TGF-β1 alone. So far, the mechanisms underlying the induction of TGF-β1-insensitive breast cancer cells remains unclear. Here we report that TNF-α can induce EMT and invasiveness of breast cancer cells which are insensitive to TGF-β1. Intriguingly, TGF-β1 could cooperate with TNF-α to promote the EMT and invasiveness of breast cancer cells. The prolonged co-stimulation with TGF-β1 and TNF-α could enhance the sustained activation of Smad2/3, p38 MAPK, ERK, JNK and NF-κB pathways by enhancing the activation of TAK1, which was mediated by the gradually up-regulated TβRs. Except for JNK, all of these pathways were required for the effects of TGF-β1 and TNF-α. Importantly, the activation of p38 MAPK and ERK pathways resulted in a positive feed-back effect on TAK1 activation by up-regulating the expression of TβRs, favoring the activation of multiple signaling pathways. Moreover, SLUG was up-regulated and required for the TGF-β1/TNF-α-induced EMT and invasiveness. In addition, SLUG could also enhance the activation of signaling pathways by promoting TβRII expression. These findings suggest that the up-regulation of TβRs contributes to the sustained activation of TAK1 induced by TGF-β1/TNF-α and the following activation of multiple signaling pathways, resulting in EMT and invasiveness of breast cancer cells.
转化生长因子-β1（TGF-β1）是上皮-间质转化（EMT）的主要诱导因子。然而，许多乳腺癌细胞对单独的TGF-β1诱导的EMT并不敏感。迄今为止，TGF-β1不敏感的乳腺癌细胞诱导的潜在机制仍不清楚。在此我们报告，肿瘤坏死因子-α（TNF-α）可诱导对TGF-β1不敏感的乳腺癌细胞发生EMT和侵袭。有趣的是，TGF-β1可与TNF-α协同促进乳腺癌细胞的EMT和侵袭。TGF-β1和TNF-α的延长共刺激可通过增强TAK1的激活来增强Smad2/3、p38丝裂原活化蛋白激酶（MAPK）、细胞外信号调节激酶（ERK）、c-Jun氨基末端激酶（JNK）和核因子-κB（NF-κB）信号通路的持续激活，这是由逐渐上调的TGF-β受体（TβRs）介导的。除JNK外，所有这些信号通路都是TGF-β1和TNF-α发挥作用所必需的。重要的是，p38 MAPK和ERK信号通路的激活通过上调TβRs的表达对TAK1激活产生正反馈作用，有利于多种信号通路的激活。此外，锌指蛋白Snail（SLUG）被上调，并且是TGF-β1/TNF-α诱导的EMT和侵袭所必需的。此外，SLUG还可通过促进TβRII的表达来增强信号通路的激活。这些发现表明，TβRs的上调有助于TGF-β1/TNF-α诱导的TAK1的持续激活以及随后多种信号通路的激活，从而导致乳腺癌细胞的EMT和侵袭。
