环状 RNA 失调连接物（circDLST）通过海绵吸附 miR-502-5p 并激活 NRAS/MEK1/ERK1/2 信号通路促进胃癌的发生和转移。
CircDLST promotes the tumorigenesis and metastasis of gastric cancer by sponging miR-502-5p and activating the NRAS/MEK1/ERK1/2 signaling.
机构信息
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.
出版信息
Mol Cancer. 2019 Apr 5;18(1):80. doi: 10.1186/s12943-019-1015-1.
BACKGROUND
Accumulating evidence shows that, the dysregulation of circular RNAs (circRNAs) is associated with the progression of multiple malignancies. But, the underlying mechanisms by which has_circ_0032627 (circDLST) contributed to gastric cancer (GC) remain undocumented.
METHODS
The expression and cellular localization of circDLST and its association with clinicopathological characteristics and prognosis in patients with GC was analysed by using fluorescence in situ hybridization. Gain- and loss-of-function experiments as well as a subcutaneous xenograft tumor model and a liver metastasis model from orthotopic implantation of GC tissues were conducted to assess the role of circDLST in GC cells. CircDLST specific binding with miR-502-5p was confirmed by dual luciferase gene report, RNA immunoprecipitation (RIP) assays and RIP-miRNA expression profiling. qRT-PCR and Western blot analysis was used to detect the effects of circDLST on miR-502-5p-mediated NRAS/MEK1/ERK1/2 signaling in GC cells.
RESULTS
The expression levels of circDLST were dramatically elevated in GC tissues as compared with the adjacent normal tissues, and acted as an independent prognostic factor of poor survival in patients with GC. Knockdown of circDLST inhibited the cell viability, colony formation, DNA synthesis, cell invasion and liver metastasis in vitro and in vivo, whereas overexpression of circDLST had the opposite effects. Furthermore, circDLST was co-localized with miR-502-5p in the cytoplasm of GC cells, and acted as a sponge of miR-502-3p in GC cells, which abrogated the tumor promoting effects of circDLST by inactivating the NRAS/MEK1/ERK1/2 signaling in GC cells.
CONCLUSION
CircDLST promotes the tumorigenesis and metastasis of GC cells by sponging miR-502-5p to activate the NRAS/MEK1/ERK1/2 signaling.
背景
越来越多的证据表明，环状 RNA（circRNAs）的失调与多种恶性肿瘤的进展有关。但是，has_circ_0032627（circDLST）促进胃癌（GC）的潜在机制尚未有报道。
方法
通过荧光原位杂交分析 circDLST 的表达和细胞定位及其与 GC 患者临床病理特征和预后的关系。通过 gain-和 loss-of-function 实验以及皮下异种移植肿瘤模型和 GC 组织原位植入的肝转移模型，评估 circDLST 在 GC 细胞中的作用。通过双荧光素酶基因报告、RNA 免疫沉淀（RIP）测定和 RIP-miRNA 表达谱分析证实 circDLST 与 miR-502-5p 的特异性结合。qRT-PCR 和 Western blot 分析用于检测 circDLST 对 GC 细胞中 miR-502-5p 介导的 NRAS/MEK1/ERK1/2 信号的影响。
结果
与相邻正常组织相比，GC 组织中 circDLST 的表达水平显著升高，并且是 GC 患者生存不良的独立预后因素。circDLST 的敲低抑制了 GC 细胞在体外和体内的细胞活力、集落形成、DNA 合成、细胞侵袭和肝转移，而过表达 circDLST 则产生相反的效果。此外，circDLST 在 GC 细胞的细胞质中与 miR-502-5p 共定位，并在 GC 细胞中作为 miR-502-5p 的海绵，通过使 GC 细胞中的 NRAS/MEK1/ERK1/2 信号失活来消除 circDLST 的促肿瘤作用。
结论
circDLST 通过海绵吸附 miR-502-5p 来激活 NRAS/MEK1/ERK1/2 信号，促进 GC 细胞的肿瘤发生和转移。
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