Inhibition of transforming growth factor beta/SMAD signal by MiR-155 is involved in arsenic trioxide-induced anti-angiogenesis in prostate cancer.
Bottom Line: Furthermore, As2 O3 improved the expression of miR-155 via DNA-demethylation.MiR-155, which targeted the SMAD2-3'UTR, decreased the expression and function of SMAD2.Knockdown of miR-155 abolished the As2 O3 -induced inhibitions of the TGF-β/SMAD2 signaling, the vascular endothelial growth factor secretion and angiogenesis.
Affiliation: Affiliated Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China.Show MeSH
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Mentions: The TGF-β/SMAD signal pathway plays an important role in the VEGF secretion in human prostate carcinoma cells.(2) We first examined the effects of As2O3 on the activation of SMAD2 and SMAD3 in TGF-β1-treated PC-3 cells. As shown in Figure 2(a), As2O3 blocked the TGF-β1-induced elevation of p-SMAD2, p-SMAD3 and VEGF (a downstream factor regulated by TGF-β(16,17)) in a dose-dependent manner. Moreover, As2O3 also attenuated the TGF-β1-induced increased expression of VEGF mRNA in PC-3 and LNCaP cells (Fig. 2b). Next, we determined the effects of As2O3 on the expressions/activations of endogenous SMAD2 and SMAD3 in prostate carcinoma cells. Our data showed that either As2O3 or SB431542 (TGF-β type I receptor inhibitor) could decrease the activations of endogenous TGFβ/SMAD signal (Fig. S2, as determined by the phosphorylation of SMAD2 and the expression/secretion of VEGF) and (Fig. 2c–e, as determined by phosphorylation of SMAD2/3 and the expressions of PAI-1 and SMAD7, two faithful target genes of TGF-β signal). Moreover, As2O3 also decreased the expressions of total SMAD2 and SMAD3 proteins and mRNA (Fig. 2c,f,g). These results indicate that As2O3 inhibits the TGF-β-SMAD signal pathway in PC-3 and LNCaP cells, and that the repressive effects of As2O3 on the endogenous SMAD2/3 may be mediated by the microRNA (miRNA).
Affiliation: Affiliated Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China.