Guangdong Key Laboratory for Genome Stability & Disease Prevention, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine , Shenzhen, Guangdong, China.
Department of Pathology, Guangdong Province Key Laboratory of Molecular Oncologic Pathology , Guangzhou, Guangdong, China.
Cell Cycle. 2020 Oct;19(20):2720-2733. doi: 10.1080/15384101.2020.1826632. Epub 2020 Oct 5.
The poor prognosis of late gastric carcinomas (GC) underscores the necessity to identify novel biomarkers for earlier diagnosis and effective therapeutic targets. MiRNA-324-5p has been shown to be over-expressed in GC, however the biological function of miRNA-324-5p implicated in gastric cancer and its downstream targets were not well understood. Wnt/β-catenin signaling pathway is aberrantly regulated in GC. We sought to explore if miRNA-324-5p promotes oncogenesis through modulating Wnt signaling and EMT. MiRNA-324-5p is highly expressed in GC based on qRT-PCR and TCGA data. In addition, in vitro cell proliferation, cell migration assays and in vivo animal exenograft were executed to show that miRNA-324-5p is an oncogenic miRNA in GC. MiRNA-324-5p activates Wnt signaling and induces EMT in GC. Further, SUFU was identified as a target of miRNA-324-5p confirmed by western blotting and luciferase assays. Spearson analysis and TCGA data indicate that the expression of SUFU is negatively associated with the expression of miRNA-324-5p. Rescue experiments were performed to determine if SUFU mediates the Wnt activation, EMT and oncogenic function of miRNA-324-5p. MiRNA-324-5p inhibitors plus SUFU siRNAs rescue partially the inhibitory effect on Wnt signaling and EMT caused by miRNA-324-5p inhibitors. Finally, the suppression of cell proliferation, migration, and colony formation ability induced by miRNA-324-5p inhibitors is alleviated by addition of SUFU siRNAs. In summary, miRNA-324-5p is overexpressed and exerts cell growth and migration-promoting effects through activating Wnt signaling and EMT by targeting SUFU in GC. It represents a potential miRNA with an oncogenic role in human gastric cancer.
晚期胃癌（GC）的预后较差，这凸显了有必要寻找新的生物标志物用于早期诊断和有效的治疗靶点。miRNA-324-5p 在 GC 中表达上调，但 miRNA-324-5p 在胃癌中的生物学功能及其下游靶点尚不清楚。Wnt/β-catenin 信号通路在 GC 中异常调节。我们试图探讨 miRNA-324-5p 是否通过调节 Wnt 信号和 EMT 促进肿瘤发生。qRT-PCR 和 TCGA 数据分析显示，miRNA-324-5p 在 GC 中高表达。此外，进行了体外细胞增殖、细胞迁移实验和体内动物异种移植实验，结果表明 miRNA-324-5p 是 GC 的致癌 miRNA。miRNA-324-5p 激活 Wnt 信号并诱导 GC 中的 EMT。进一步通过 Western blot 和荧光素酶报告基因实验证实 SUFU 是 miRNA-324-5p 的靶基因。Spearson 分析和 TCGA 数据表明，SUFU 的表达与 miRNA-324-5p 的表达呈负相关。进行了挽救实验以确定 SUFU 是否介导 miRNA-324-5p 的 Wnt 激活、EMT 和致癌功能。miRNA-324-5p 抑制剂加 SUFU siRNA 部分挽救了 miRNA-324-5p 抑制剂对 Wnt 信号和 EMT 的抑制作用。最后，通过添加 SUFU siRNA，减轻了 miRNA-324-5p 抑制剂诱导的细胞增殖、迁移和集落形成能力的抑制作用。总之，miRNA-324-5p 在 GC 中过度表达，通过靶向 SUFU 激活 Wnt 信号和 EMT，发挥促进细胞生长和迁移的作用。它代表了一种在人类胃癌中具有致癌作用的潜在 miRNA。
