3Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, West Changle Road, Xi'an 710032, China. K. W.,
FASEB J. 2013 Dec;27(12):4929-39. doi: 10.1096/fj.13-233387. Epub 2013 Aug 27.
Epigenetic changes play significant roles in the development of cancer. UHRF1, as an epigenetic regulator, has been shown to be overexpressed and to coordinate tumor suppressor gene silencing in several cancers. However, the role and underlying mechanism of UHRF1 in gastric cancer (GC) progression remain largely unknown. In this study, we investigated the expression and function of UHRF1 in GC metastasis and explored its upstream regulatory mechanisms at the microRNA level. UHRF1 was overexpressed in GC tissues, especially in metastatic ones, and a high level of UHRF1 expression predicted poor survival. The down-regulation of UHRF1 suppressed GC invasion and metastasis in vitro and in vivo. We identified and verified miR-146a and miR-146b as direct upstream regulators of UHRF1. Furthermore, the restoration of miR-146a/b dramatically reduced the expression of UHRF1 through the direct targeting of its 3'-UTR, and this effect in turn reactivated the slit homologue 3 (Slit3), cadherin 4 (CDH4), and runt-related transcription factor 3 (RUNX3) genes via promoter demethylation. Finally, analyses of miR-146a/b and UHRF1 levels in human GC tissues revealed that miR-146a/b correlated inversely with UHRF1 expression. These findings describe a new mechanism for the regulation of UHRF1 and aberrant DNA hypermethylation in GC. The newly identified miR-146a/b/UHRF1 axis provides insight into the GC metastasis process, and targeting this novel axis represents a therapeutic approach to blocking GC metastasis.
表观遗传改变在癌症的发展中起着重要作用。UHRF1 作为一种表观遗传调节剂，已被证明在多种癌症中过表达，并协调肿瘤抑制基因的沉默。然而，UHRF1 在胃癌（GC）进展中的作用及其潜在机制在很大程度上仍不清楚。在本研究中，我们研究了 UHRF1 在 GC 转移中的表达和功能，并探讨了其在 miRNA 水平上的上游调控机制。UHRF1 在 GC 组织中表达上调，特别是在转移性组织中，高水平的 UHRF1 表达预示着预后不良。UHRF1 的下调抑制了 GC 在体外和体内的侵袭和转移。我们鉴定并验证了 miR-146a 和 miR-146b 是 UHRF1 的直接上游调控因子。此外，miR-146a/b 的恢复通过直接靶向其 3'-UTR 显著降低了 UHRF1 的表达，这种作用反过来又通过启动子去甲基化重新激活了缝隙同源物 3（Slit3）、钙粘蛋白 4（CDH4）和 runt 相关转录因子 3（RUNX3）基因。最后，对人类 GC 组织中 miR-146a/b 和 UHRF1 水平的分析表明，miR-146a/b 与 UHRF1 表达呈负相关。这些发现描述了一种新的调节 UHRF1 和 GC 中异常 DNA 高甲基化的机制。新鉴定的 miR-146a/b/UHRF1 轴为 GC 转移过程提供了深入了解，并针对该新轴代表了阻断 GC 转移的治疗方法。
