Zou Jixue, Zhou Zhigang, Wan Liping, Tong Yin, Qin Youwen, Wang Chun, Zhou Kun
Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
Department of Intensive Care Unit, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
PLoS One. 2015 Aug 28;10(8):e0136843. doi: 10.1371/journal.pone.0136843. eCollection 2015.
The complex mechanistic array underlying the pathogenesis of myelodysplastic syndrome (MDS) is still unclear. Although dysregulations of different signaling pathways involved in MDS have been described, the identification of specific biomarkers and therapy targets remains an important task in order to establish novel therapeutic approaches. Here, we demonstrated that the Shh signaling pathway is active in MDS and correlated it with disease progression. Additionally, the knockdown of Gli1 significantly inhibited cell proliferation in vitro and in vivo. Gli1 silencing also induced apoptosis and G0/G1 phase arrest. Furthermore, Gli1 silencing enhanced the demethylating effect of 5-aza-2'-deoxycytidine on the p15 gene promoter and subsequently promoted its expression by inhibiting DNA methyltransferase 1(DNMT1). Our findings show that the Shh signaling pathway plays a role in the pathogenesis and disease progression of MDS, and proceeds by modulating DNA methylation. This pathway may prove to be a potential therapeutic target for enhancing the therapeutic effects of 5-azacytidine on malignant transformation of MDS.
骨髓增生异常综合征（MDS）发病机制背后复杂的机制阵列仍不清楚。尽管已经描述了MDS中涉及的不同信号通路的失调，但为了建立新的治疗方法，鉴定特定的生物标志物和治疗靶点仍然是一项重要任务。在此，我们证明Shh信号通路在MDS中是活跃的，并将其与疾病进展相关联。此外，Gli1的敲低在体外和体内均显著抑制细胞增殖。Gli1沉默还诱导细胞凋亡和G0/G1期阻滞。此外，Gli1沉默增强了5-氮杂-2'-脱氧胞苷对p15基因启动子的去甲基化作用，并随后通过抑制DNA甲基转移酶1（DNMT1）促进其表达。我们的研究结果表明，Shh信号通路在MDS的发病机制和疾病进展中起作用，并通过调节DNA甲基化发挥作用。该通路可能被证明是增强5-氮杂胞苷对MDS恶性转化治疗效果的潜在治疗靶点。
