TGF-β1 and TNF-α synergistically induce epithelial to mesenchymal transition of breast cancer cells by enhancing TAK1 activation
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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.
KeywordsTGF-β1 TNF-α TAK1 EMT Invasion
Epithelial to mesenchymal transition
Extracellular signal-regulated kinase
C-Jun N-terminal kinase
Mitogen activated protein kinases
Nuclear factor kappa-light-chain-enhancer of activated B cells
Transforming growth factor-β activated kinase 1
Transforming growth factor-β1
Tumor necrosis factor-α
Transforming growth factor-β receptor type I
Transforming growth factor-β receptor type II
We gratefully thank Prof. Xing-Zhen Chen (Department of Physiology, University of Alberta, Canada) and Dr. Feng-Hua Wu (Department of Physiology, Hubei University of Chinese Medcine, China) for modifying the manuscript and their valuable advice.
SJL and ZHF conceived and designed the experiments; SJL, JL, DL, YHZ, BY and JJW performed the experiment. JCT, YRL and GMZ interpreted and analyzed the data; SJL and ZHF wrote the manuscript. All authors read and approved the final manuscript.
This work was supported by National Natural Science Foundation of China (No.81472704, 81272314, 30830095), National Development Program (973) For Key Basic Research of China (No. 2009CB521806).
Compliance with ethical standards
The authors declare that they have no competing interests.
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