Li Zheng-Tian, Zhang Xu, Wang Da-Wei, Xu Jun, Kou Ke-Jian, Wang Zhi-Wei, Yong Gong, Liang De-Sen, Sun Xue-Ying
Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, P.R. China.
The Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, P.R. China; Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, P.R. China.
Mol Ther Nucleic Acids. 2020 Mar 6;19:827-840. doi: 10.1016/j.omtn.2019.09.034. Epub 2019 Nov 22.
Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. Accumulating evidence reveals the significance of long non-coding RNAs (lncRNAs) in various cancers. The current study aimed to evaluate the role of GATA6 antisense RNA 1 (GATA6-AS1) in the epithelial-mesenchymal transition (EMT) and lymph node metastasis (LNM) in GC. GC-related microarray datasets were initially retrieved from the GEO with differentially expressed lncRNAs screened, followed by evaluation of the regulatory relationship between Frizzled 4 (FZD4) and GATA6-AS1. The detailed regulatory mechanism by which GATA6-AS1 influences the Wnt/β-catenin signaling pathway and GC cell biological behaviors was investigated by treating SGC7901 cells with overexpressed GATA6-AS1, specific antisense oligonucleotide against GATA6-AS1, and lithium chloride (LiCl; activator of the Wnt/β-catenin signaling pathway). Finally, xenograft nude mice were used to assay tumor growth and LNM in vivo. GATA6-AS1 was poorly expressed, but FZD4 was highly expressed in GC tissues and cells. Elevated GATA6-AS1 reduced FZD4 expression by recruiting enhancer of zeste homolog 2 (EZH2) and trimethylation at lysine 27 of histone H3 (H3K27me3) to the FZD4 promoter region via the inactivated Wnt/β-catenin signaling pathway, whereby cell invasion, migration, and proliferation, tumor growth, and LNM in nude mice were reduced. Taken together, overexpressed GATA6-AS1 downregulated the expression of FZD4 to inactivate the Wnt/β-catenin signaling pathway, which ultimately inhibited GC progression.
胃癌（GC）是全球癌症相关死亡的主要原因之一。越来越多的证据揭示了长链非编码RNA（lncRNA）在各种癌症中的重要性。本研究旨在评估GATA6反义RNA 1（GATA6-AS1）在GC上皮-间质转化（EMT）和淋巴结转移（LNM）中的作用。首先从基因表达综合数据库（GEO）中检索GC相关的微阵列数据集，筛选差异表达的lncRNA，随后评估卷曲蛋白4（FZD4）与GATA6-AS1之间的调控关系。通过用过表达的GATA6-AS1、针对GATA6-AS1的特异性反义寡核苷酸和氯化锂（LiCl；Wnt/β-连环蛋白信号通路激活剂）处理SGC7901细胞，研究GATA6-AS1影响Wnt/β-连环蛋白信号通路和GC细胞生物学行为的详细调控机制。最后，利用异种移植裸鼠在体内检测肿瘤生长和LNM。GATA6-AS1在GC组织和细胞中低表达，但FZD4高表达。通过使Wnt/β-连环蛋白信号通路失活，升高的GATA6-AS1通过招募zeste同源物2（EZH2）增强子和组蛋白H3赖氨酸27（H3K27me3）三甲基化至FZD4启动子区域来降低FZD4表达，从而减少裸鼠中的细胞侵袭、迁移和增殖、肿瘤生长及LNM。综上所述，过表达的GATA6-AS1下调FZD4表达以使Wnt/β-连环蛋白信号通路失活，最终抑制GC进展。
