Nuclear cytokine-activated IKKa controls prostate cancer metastasis by repressing Maspin

Nature, 446(7136):690, 2007¹

Speaker: 沈郁婷                                           Date: 05/09/2007; 15:10

Commentator: 徐麗君 老師                                 Place: Room 601

Abstract:

In recent years it has become clear that inflammation and a proinflammatory microenvironment make important and critical contributions to tumor development. Mechanistic studies revealed the significance of the transcription factor nuclear factor κB (NFκB) and its activating IκB kinases (IKKα and β) in cancer progression via their ability to differentially regulate cell survival and production of proinflammatory cytokines². Maspin is a tumor suppressor whose expression is lost in many advanced breast cancers. Previously studies show that, aberrant cytosine methylation and heterochromatinization of the maspin promoter may silence maspin gene expression to inhibit cell motility, invasion, and metastasis³. In this paper, the authors used TRAMP mice, a transgenic mouse model of prostate cancer in which the SV40 large T antigen is selectively expressed in prostate epithelium, and IKKα^AA/AA/TRAMP mice harboring an inactive IKKα, and found that IKKα is a key mediator of the interplay between inflammation and metastasis in prostate cancer. IKKα^AA/AA/TRAMP mice exhibited considerably fewer distant site metastases and lower maspin expression than wild-type TRAMP mice. The authors evidenced prostate cancer metastasis is a consequence of tumor infiltration by RANKL- expressing inflammatory cells that activate IKKα in the nuclei of carcinoma cells to repress Maspin transcription.

References:

1. Luo JL et al. Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature 2007; 446:690-4

2. Greenberg NM et al. Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA 1995; 92:3439-43

3. Affara NI et al. IKKα at the crossroads of inflammation and metastasis. Cell 2007; 129:25-6

4. Domann FE et al. Epigenetic silencing of maspin gene expression in human breast cancers. Int J Cancer 2000; 85:805-10