Abstract
Maspin is a member of the clade B serine protease inhibitor superfamily and exhibits diverse regulatory effects in various types of solid tumors. We compared the expressions of maspin and determined its potential biological functions and regulatory mechanisms in bladder carcinoma cells in vitro and in vivo. The results of RT-qPCR indicated that maspin expressed significantly lower levels in the bladder cancer tissues than in the paired normal tissues. The immunohistochemical assays of human bladder tissue arrays revealed similar results. Maspin-knockdown enhanced cell invasion whereas the overexpression of maspin resulted in the opposite process taking place. Knockdown of maspin also enhanced tumorigenesis in vivo and downregulated protein levels of acetyl-histone H3. Moreover, in bladder carcinoma cells, maspin modulated HDAC1 target genes, including cyclin D1, p21, MMP9, and vimentin. Treatment with MK2206, which is an Akt inhibitor, upregulated maspin expression, whereas PTEN-knockdown or PTEN activity inhibitor (VO-OHpic) treatments demonstrated reverse results. The ectopic overexpression of p53 or camptothecin treatment induced maspin expression. Our study indicated that maspin is a PTEN-upregulated and p53-upregulated gene that blocks cell growth in vitro and in vivo, and may act as an HDAC1 inhibitor in bladder carcinoma cells. We consider that maspin is a potential tumor suppressor gene in bladder cancer.
Highlights
A recent epidemiologic study indicated that bladder cancer is the 9th most common cancer worldwide [1]
The RT-qPCR analysis of paired human bladder tissues revealed that the mean of ∆∆cycle threshold (Ct) was 1.9812 ± 0.7575 and 2.0258 ± 0.7701
Reports concerning the biological function of maspin in bladder cancer are still contradictory, our previous studies have indicated that maspin is the downstream gene of the prostate-derived Ets factor (PDEF) and growth differentiation factor 15 (GDF15), which are antitumor genes in bladder carcinoma cells [18,19]
Summary
A recent epidemiologic study indicated that bladder cancer is the 9th most common cancer worldwide [1]. Some studies have indicated that maspin expression can play a possible clinical role as a novel tumor suppressor gene in the bladder’s transitional cell carcinoma and can be a useful prognostic marker for predicting the tumor behavior in stage T1 bladder tumors [7,8]. Maspin may contribute to bladder cancer development because its expression is positively correlated with the tumor grade [10,11]. These contrary results are confirmed by in vivo immunohistochemical (IHC) assays and by in vitro cell models from different laboratories. One study revealed that RT-4 cells are maspin-negative [11]
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