Poster Presentation 25th Lorne Cancer Conference 2013

Transcription Factor ATF3 Suppresses Bladder Cancer Metastases by Regulating Gelsolin-Mediated Actin Cytoskeleton Remodeling (#411)

Xiangliang Yuan 1 , Liang Yu 2 , Bryan R.G. Williams 2 , Lisong Shen 1 , Dakang Xu 2
  1. Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
  2. Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute, clayton, vic, Australia

Bladder cancer is associated with high recurrence and mortality rates due to metastases. The discovery of metastases suppressors offers significant therapeutic opportunities, but their mechanisms of action have yet to be fully elucidated. Here we investigate the clinical and functional significance of activating transcription factor 3 (ATF3) expression in bladder cancer metastasis. Analysis of tissue microarrays revealed that decreased ATF3 expression was associated with increased bladder cancer metastatic status and reduced survival of patients with bladder cancer. Correspondingly, overexpression of ATF3 in a high-metastatic potential bladder cancer cell line decreased cell migration in vitro and metastasis in vivo. Conversely, depletion of ATF3 increased the migration of low-metastatic potential bladder cancer cells, but with no effect on proliferation. In keeping with their increased motility, metastatic bladder cancer cells had increased numbers of actin filaments. Moreover, the expression levels of ATF3 in bladder cancers correlated with the expression of the actin-modifying protein gelsolin (GSN). Expression of ATF3 upregulated GSN in bladder cancer cells, while knockdown of ATF3 reduced the levels of GSN, concomitant with alterations in the actin cytoskeleton. Furthermore, six putative ATF3 regulatory elements were identified within the first intron of the GSN gene and confirmed by chromatin immunoprecipitation assays. Critically, expression of GSN reversed the metastasis of bladder cancer cells with diminished ATF3. Taken together, our results suggest that ATF3 suppresses metastasis of bladder cancer cells, at least in part, via upregulation of GSN-mediated actin remodeling. These findings advocate ATF3 coupled with GSN as prognostic markers for bladder cancer metastasis.