Stabilization of Snail by NF-kB Is Required for Inflammation-Induced Cell Migration and Invasion

Yadi Wu, Jiong Deng, Piotr G. Rychahou, Suimin Qiu, B. Mark Evers, and Binhua P. Zhou
Cancer Cell 15, 416–428 (2009)

Speaker: Yu-Hong Chen (陳俞宏)                        Time: 14:00~15:00 Nov. 4, 2009

Commentator: Dr. Yao Chang (張堯博士)           Place: Room 601

Abstract:

The causal relationship between inflammation and cancer is more widely accepted. Tumor-associated macrophages (TAMs) are usually found at the invasive front (the tumor-host interface) of advanced tumors and thus were thought to promote tumor cell motility¹. Epithelial-mesenchymal transition (EMT) is the process that cells reduce intercellular adhesion and increase motility in many metastatic cancers. Snail, a short half-life transcription factor, has been reported in controlling EMT² and aberrantly expressed in human cancers³. In this paper, the authors hypothesize that motility of tumor cells is induced by inflammation through Snail-mediated EMT induction. They found that invasive ability of tumor cells was greatly increased in macrophage-conditioned medium than in regular culture medium. Further results clarified that TNF-a was the major cytokine that macrophage secreted to stabilize Snail. Next, they used NF-kB inhibitor, immunofluorescent staining, and various deletion mutants of p65 coexpressed with Snail to demonstrate that activation and transcriptional activity of NF-kB contributed to TNF-a-mediated Snail stabilization. Furthermore, NF-kB was required for the induction of COP9 signalosome 2 (CSN2), which, in turn, blocked the ubiquitination and degradation of Snail. Snail was involved in cell migration, invasion, and metastasis mediated by inflammation with wound healing assay and LPS-induced inflammatory mouse model. In summary, these results demonstrate that inflammation-induced migration, invasion, and metastasis of tumor cells are regulated through NF-kB-mediated Snail stabilization.

References:

1. Condeelis, J., and Pollard, J.W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).

2. Nieto, M.A. The snail superfamily of zinc-finger transcription factors. Nat. Rev. Mol. Cell Biol. 3, 155–166 (2002).

3. Kajita, M., McClinic, K.N., and Wade, P.A. Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol. Cell. Biol. 24, 7559–7566 (2004).