Zhang Yu, Huang Zhen, Zhu Zhiqiang, Zheng Xin, Liu Jianwei, Han Zhiyou, Ma Xuetao, Zhang Yuhai
Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Department of Urology, Beijing You An Hospital, Capital Medical University, Beijing, China.
Department of Urology, Beijing You An Hospital, Capital Medical University, Beijing, China.
PLoS One. 2014 Oct 1;9(10):e104252. doi: 10.1371/journal.pone.0104252. eCollection 2014.
Ubiquitin-like with PHD and RING finger domains 1 (UHRF1), as an epigenetic regulator, plays important roles in the tumorigenesis and cancer progression. KiSS1 functions as a metastasis suppressor in various cancers, and epigenetic silencing of KiSS1 increases the metastatic potential of cancer cells. We therefore investigated whether UHRF1 promotes bladder cancer cell invasion by inhibiting KiSS1. The expression levels of UHRF1 and KiSS1 were examined by quantitative real-time PCR assay in vitro and in vivo. The role of UHRF1 in regulating bladder cancer metastasis was evaluated in bladder cancer cell. We found that UHRF1 levels are upregulated in most clinical specimens of bladder cancer when compared with paired normal tissues, and UHRF1 expression levels are significantly increased in primary tumors that subsequently metastasized compared with non-metastatic tumors. Forced expression of UHRF1 promotes bladder cancer cell invasion, whereas UHRF1 knockdown decreases cell invasion. Overexpression of UHRF1 increases the methylation of CpG nucleotides and reduces the expression of KiSS1. UHRF1 and KiSS1 expression level is negatively correlated in vivo and in vitro. Knockdown of KiSS1 promotes bladder cancer cell invasion. Importantly, forced expression of KiSS1 partly abrogates UHRF1-induced cell invasion. These data demonstrated that upregulated UHRF1 increases bladder cancer cell invasion by epigenetic silencing of KiSS1.
含 PHD 和 RING 指结构域的类泛素蛋白 1（UHRF1）作为一种表观遗传调节因子，在肿瘤发生和癌症进展中发挥重要作用。KiSS1 在多种癌症中作为转移抑制因子发挥作用，KiSS1 的表观遗传沉默会增加癌细胞的转移潜能。因此，我们研究了 UHRF1 是否通过抑制 KiSS1 促进膀胱癌细胞侵袭。通过定量实时 PCR 分析在体外和体内检测 UHRF1 和 KiSS1 的表达水平。在膀胱癌细胞中评估 UHRF1 在调节膀胱癌转移中的作用。我们发现，与配对的正常组织相比，大多数膀胱癌临床标本中 UHRF1 水平上调，与未转移肿瘤相比，在随后发生转移的原发性肿瘤中 UHRF1 表达水平显著增加。UHRF1 的强制表达促进膀胱癌细胞侵袭，而 UHRF1 的敲低则降低细胞侵袭。UHRF1 的过表达增加 CpG 核苷酸的甲基化并降低 KiSS1 的表达。UHRF1 和 KiSS1 的表达水平在体内和体外均呈负相关。KiSS1 的敲低促进膀胱癌细胞侵袭。重要的是，KiSS1 的强制表达部分消除了 UHRF1 诱导的细胞侵袭。这些数据表明，上调的 UHRF1 通过 KiSS1 的表观遗传沉默增加膀胱癌细胞侵袭。
