Abstract
The increased motility and invasiveness of tumor cells are reminiscent of epithelial-mesenchymal transition (EMT), which occurs during embryonic development, wound healing, and metastasis. In this study, we found that Snail is stabilized by the inflammatory cytokine TNFalpha through the activation of the NF-kappaB pathway. We demonstrated that NF-kappaB is required for the induction of COP9 signalosome 2 (CSN2), which, in turn, blocks the ubiquitination and degradation of Snail. Furthermore, we showed that the expression of Snail correlated with the activation of NF-kappaB in cancer cell lines and metastatic tumor samples. Knockdown of Snail expression inhibited cell migration and invasion induced by inflammatory cytokines and suppressed inflammation-mediated breast cancer metastasis. Our study provides a plausible mechanism for inflammation-induced metastasis.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
COP9 Signalosome Complex
-
Cell Line, Tumor
-
Cell Movement* / physiology
-
Cell Transformation, Neoplastic / metabolism
-
Female
-
Glycogen Synthase Kinase 3 / antagonists & inhibitors
-
Glycogen Synthase Kinase 3 beta
-
Humans
-
Inflammation / metabolism
-
Macrophages / metabolism*
-
Macrophages / pathology
-
Mice
-
Multiprotein Complexes / metabolism
-
NF-kappa B / metabolism*
-
Neoplasm Invasiveness
-
Neoplasm Metastasis
-
Neoplasms / metabolism
-
Neoplasms / pathology
-
Peptide Hydrolases / metabolism
-
SKP Cullin F-Box Protein Ligases / antagonists & inhibitors
-
Signal Transduction
-
Snail Family Transcription Factors
-
Transcription Factors / metabolism*
-
Tumor Necrosis Factor-alpha / metabolism
Substances
-
Multiprotein Complexes
-
NF-kappa B
-
Snail Family Transcription Factors
-
Transcription Factors
-
Tumor Necrosis Factor-alpha
-
SKP Cullin F-Box Protein Ligases
-
Glycogen Synthase Kinase 3 beta
-
Glycogen Synthase Kinase 3
-
Peptide Hydrolases
-
COP9 Signalosome Complex