Abstract：
Dysregulation of microRNAs (miRNAs or miRs) is implicated in the development of gastric cancer (GC), which is possibly related to their roles in targeting tumor-suppressive or tumor-promoting genes. Herein, the current study was intended to ascertain the function of miR-488 and its modulatory mechanism in GC. Initially, human GC cells were assayed for their in vitro malignancy after miRNA gain- or loss-of-function and RNA interference or overexpression. Also, tumorigenesis and liver metastasis were evaluated in nude mouse models. Results demonstrated that miR-488 elevation suppressed GC (MKN-45 and OCUM-1) cell proliferation, migration, and invasiveness in vitro and reduced their tumorigenesis and liver metastasis in vivo. The luciferase assay identified that miR-488 bound to HULC and inhibited its expression. Furthermore, HULC could enhance EZH2-H3K27me3 enrichment at the p53 promoter region and epigenetically repress the p53 expression based on the data from RIP- and ChIP-qPCR assay. Additionally, HULC was validated to enhance GC growth and metastasis in vitro and in vivo. Overall, HULC re-expression elicited by miR-488 inhibition can enhance EZH2-H3K27me3 enrichment in the p53 promoter and repress the p53 expression, thus promoting the growth and metastasis of GC.
摘要：
microRNAs（miRNAs或miRs）的失调与胃癌（GC）的发展有关。这可能与它们在靶向肿瘤抑制或肿瘤促进基因中的作用有关。在这里，本研究旨在确定miR-488的功能及其在GC中的调节机制.最初，在miRNA功能获得或丧失以及RNA干扰或过表达后，检测人GC细胞的体外恶性程度。此外，在裸鼠模型中评估肿瘤发生和肝转移。结果表明，miR-488升高抑制GC（MKN-45和OCUM-1）细胞增殖，迁移,和体外侵袭性，并减少其肿瘤发生和体内肝转移。荧光素酶测定鉴定miR-488与HULC结合并抑制其表达。此外，基于来自RIP-和ChIP-qPCR测定的数据,HULC可以增强在p53启动子区域的EZH2-H3K27me3富集并表观遗传地抑制p53表达。此外,HULC被证实在体外和体内增强GC生长和转移。总的来说,抑制miR-488引起的HULC再表达可以增强p53启动子中EZH2-H3K27me3的富集并抑制p53的表达，从而促进GC的生长和转移。
