Abstract
Bladder cancer is associated with high recurrence and mortality rates due to metastasis. The elucidation of metastasis suppressors may offer therapeutic opportunities if their mechanisms of action can be elucidated and tractably exploited. In this study, we investigated the clinical and functional significance of the transcription factor activating transcription factor 3 (ATF3) in bladder cancer metastasis. Gene expression analysis revealed that decreased ATF3 was associated with bladder cancer progression and reduced survival of patients with bladder cancer. Correspondingly, ATF3 overexpression in highly metastatic bladder cancer cells decreased migration in vitro and experimental metastasis in vivo. Conversely, ATF3 silencing increased the migration of bladder cancer cells with limited metastatic capability in the absence of any effect on proliferation. In keeping with their increased motility, metastatic bladder cancer cells had increased numbers of actin filaments. Moreover, ATF3 expression correlated with expression of the actin filament severing protein gelsolin (GSN). Mechanistic studies revealed that ATF3 upregulated GSN, whereas ATF3 silencing reduced GSN levels, concomitant with alterations in the actin cytoskeleton. We identified six ATF3 regulatory elements in the first intron of the GSN gene confirmed by chromatin immunoprecipitation analysis. Critically, GSN expression reversed the metastatic capacity of bladder cancer cells with diminished levels of ATF3. Taken together, our results indicate that ATF3 suppresses metastasis of bladder cancer cells, at least in part through the upregulation of GSN-mediated actin remodeling. These findings suggest ATF3 coupled with GSN as prognostic markers for bladder cancer metastasis.
Highlights
Despite good prognosis for bladder cancer with an early diagnosis, recurrence is common after surgical intervention and nearly half of all patients with bladder cancer harbor occult metastases that are associated with reduced survival [1]
We show that downregulation of activating transcription factor 3 (ATF3) stimulates bladder cancer cell migration in vitro and cell metastasis in vivo
ATF3 shows a positive correlation with GSN expression in the same tumors, and we show that the transcription factor ATF3 directly regulates the GSN gene through 6 putative binding sites, coincident with cell cytoskeletal depolymerization and migration of bladder cancer cells
Summary
Despite good prognosis for bladder cancer with an early diagnosis, recurrence is common after surgical intervention and nearly half of all patients with bladder cancer harbor occult metastases that are associated with reduced survival [1]. Progression to metastasis marks a significant detri-. Authors' Affiliations: Departments of 1Clinical Laboratory and 2Urology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai; 3Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, China; 4Monash Institute of Medical Research, Monash University; and 5Department of Surgery, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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