Inhibition of transforming growth factor beta/SMAD signal by MiR-155 is involved in arsenic trioxide-induced anti-angiogenesis in prostate cancer

Abstract

Prostate cancer is the most common cause of cancer-related deaths in men. Current practices for treatment of prostate cancer are less than satisfactory because of metastasis and recurrence, which are primarily attributed to angiogenesis. Hence, anti-angiogenesis treatment is becoming a promising new approach for prostate cancer therapy. In addition to treating acute promyelocytic leukemia, arsenic trioxide (As2O3) suppresses other solid tumors, including prostate cancer. However, the effects of As2O3 on angiogenesis in prostate cancer cells, and the underlying molecular mechanisms remain unclear. In the present study, As2O3 attenuated angiogenic ability through microRNA-155 (miR-155)-mediated inhibition of transforming growth factor beta (TGF-β)/SMAD signal pathway in human prostate cancer PC-3 and LNCaP cells in vitro and in vivo. Briefly, As2O3 inhibited the activations/expressions of both TGFβ-induced and endogenous SMAD2/3. Furthermore, As2O3 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 As2O3-induced inhibitions of the TGF-β/SMAD2 signaling, the vascular endothelial growth factor secretion and angiogenesis. Through understanding a novel mechanism whereby As2O3 inhibits angiogenic potential of prostate cancer cells, our study would help in the development of As2O3 as a potential chemopreventive agent when used alone or in combination with other current anticancer drugs. As2O3 improved the expression miR-155 via DNA-demethylation. As an up-stream regulator of TGF-β signaling, miR-155 decreased the expression and function of SMAD2 by targeting the SMAD2-3′UTR. Knockdown of miR-155 abolished the As2O3-induced inhibitions of the TGF-β/SMAD2 signaling, the VEGF secretion, and the angiogenesis in prostate cancer cells in vitro and in vivo.