Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600 Yishan Road, Shanghai, 200233, China.
Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Mol Cancer. 2017 Sep 11;16(1):151. doi: 10.1186/s12943-017-0719-3.
Non-coding RNAs (ncRNAs) have been shown to regulate gene expression involved in tumor progression of multiple malignancies. Our previous studies indicated that large tumor suppressor kinase 1 (LATS1), a core part of Hippo signaling pathway, functions as a tumor suppressor in gastric cancer (GC). But, the underlying molecular mechanisms by which ncRNAs modulate LATS1 expression in GC remain undetermined.
The correlation of LATS1 and has-miR-424-5p (miR-424) expression with clinicopathological characteristics and prognosis of GC patients was analyzed by TCGA RNA-sequencing data. A novel circular RNA_LARP4 (circLARP4) was identified to sponge miR-424 by circRNA expression profile and bioinformatic analysis. The binding site between miR-424 and LATS1 or circLARP4 was verified using dual luciferase assay and RNA immunoprecipitation (RIP) assay. The expression and localization of circLARP4 in GC tissues were investigated by fluorescence in situ hybridization (FISH). MTT, colony formation, Transwell and EdU assays were performed to assess the effects of miR-424 or circLARP4 on cell proliferation and invasion.
Increased miR-424 expression or decreased LATS1 expression was associated with pathological stage and unfavorable prognosis of GC patients. Ectopic expression of miR-424 promoted proliferation and invasion of GC cells by targeting LATS1 gene. Furthermore, circLARP4 was mainly localized in the cytoplasm and inhibited biological behaviors of GC cells by sponging miR-424. The expression of circLARP4 was downregulated in GC tissues and represented an independent prognostic factor for overall survival of GC patients.
circLARP4 may act as a novel tumor suppressive factor and a potential biomarker in GC.
非编码 RNA（ncRNA）已被证明可调节参与多种恶性肿瘤肿瘤进展的基因表达。我们之前的研究表明，Hippo 信号通路的核心部分——大肿瘤抑制激酶 1（LATS1）在胃癌（GC）中作为肿瘤抑制因子发挥作用。但是，ncRNA 调节 GC 中 LATS1 表达的潜在分子机制尚不清楚。
通过 TCGA RNA 测序数据分析 LATS1 和 has-miR-424-5p（miR-424）表达与 GC 患者临床病理特征和预后的相关性。通过 circRNA 表达谱和生物信息学分析鉴定了一种新型环状 RNA_LARP4（circLARP4），该环状 RNA 可通过海绵吸附 miR-424。使用双荧光素酶报告基因检测和 RNA 免疫沉淀（RIP）实验验证 miR-424 与 LATS1 或 circLARP4 的结合位点。通过荧光原位杂交（FISH）实验研究 GC 组织中 circLARP4 的表达和定位。通过 MTT、集落形成、Transwell 和 EdU 实验评估 miR-424 或 circLARP4 对细胞增殖和侵袭的影响。
miR-424 表达增加或 LATS1 表达降低与 GC 患者的病理分期和不良预后相关。过表达 miR-424 通过靶向 LATS1 基因促进 GC 细胞的增殖和侵袭。此外，circLARP4 主要定位于细胞质中，通过海绵吸附 miR-424 抑制 GC 细胞的生物学行为。circLARP4 在 GC 组织中的表达下调，并代表 GC 患者总生存的独立预后因素。
circLARP4 可能作为 GC 的新型肿瘤抑制因子和潜在的生物标志物发挥作用。
