Regulation of SLD5 gene expression by miR-370 during acute growth of cancer cells.
Regulation of SLD5 gene expression by miR-370 during acute growth of cancer cells.
复制标题
DOI：
10.1038/srep30941
复制
发表时间：
2016-08-08
影响因子：
4.6
通讯作者：
Takakura N
中科院分区：
文献类型：
--
作者：
Yamane K;Naito H;Wakabayashi T;Yoshida H;Muramatsu F;Iba T;Kidoya H;Takakura N
SLD 5是GINS复合物的成员，对真核生物中的DNA复制至关重要。据报道，SLD 5参与小鼠的早期胚胎发生，以及果蝇的细胞周期进程和基因组完整性。SLD 5可能参与恶性肿瘤的进展，但其在人类癌症中的相关性尚未确定。在这里，我们发现SLD 5在来自患者和细胞系的人膀胱癌组织中均强烈表达。使用小干扰RNA敲低SLD 5导致体外和体内异种移植模型中细胞生长的减少。此外，我们发现膀胱癌细胞中高水平的SLD 5是由于microRNA（miR）-370的下调，否则会抑制其表达。DNA甲基转移酶（DNMT）1和IL-6在膀胱癌细胞中也有高水平表达。IL-6的敲低导致DNMT 1和SLD 5表达下调，表明IL-6诱导的DNMT 1过表达抑制miR-370，导致SLD 5高表达。我们的研究结果可能有助于了解人类膀胱癌的致瘤过程和进展，因此抑制SLD 5可能代表一种预防肿瘤生长的新策略。
SLD5 is a member of the GINS complex, essential for DNA replication in eukaryotes. It has been reported that SLD5 is involved in early embryogenesis in the mouse, and cell cycle progression and genome integrity in Drosophila. SLD5 may be involved in malignant tumor progression, but its relevance in human cancer has not been determined. Here, we found strong SLD5 expression in both human bladder cancer tissues from patients and cell lines. Knockdown of SLD5 using small interfering RNA resulted in reduction of cell growth both in vitro and an in vivo xenograft model. Moreover, we found that high levels of SLD5 in bladder cancer cells result from downregulation of microRNA (miR)-370 that otherwise suppresses its expression. High level expression of DNA-methyltransferase (DNMT) 1 and IL-6 were also observed in bladder cancer cells. Knockdown of IL-6 led to downregulation of DNMT1 and SLD5 expression, suggesting that IL-6-induced overexpression of DNMT1 suppresses miR-370, resulting in high SLD5 expression. Our findings could contribute to understanding tumorigenic processes and progression of human bladder cancer, whereby inhibition of SLD5 could represent a novel strategy to prevent tumor growth.