Linc-SCRG1 accelerates progression of hepatocellular carcinoma as a ceRNA of miR26a to derepress SKP2.
Linc-SCRG1 accelerates progression of hepatocellular carcinoma as a ceRNA of miR26a to derepress SKP2.
复制标题
Linc-SCRG1 作为 miR26a 的 ceRNA 去抑制 SKP2，加速肝细胞癌的进展
DOI：
10.1186/s13046-020-01825-2
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发表时间：
2021-01-09
期刊：
影响因子：
--
通讯作者：
Xu MY
中科院分区：
文献类型：
--
作者：
Hu JJ;Zhou C;Luo X;Luo SZ;Li ZH;Xu ZX;Xu MY
背景
越来越多的证据表明长链非编码RNA（lncRNA）在肝细胞癌（HCC）中具有调控功能。lincSCRG 1和HCC之间的联系尚不清楚。
方法
为了探索lincSCRG 1调控轴，进行生物信息学、RIP和荧光素酶报告基因分析。通过qPCR和western blot检测肝癌组织和细胞系中lincSCRG 1-miR 26 a-SKP 2的表达。通过MTT法、集落形成法、transwell法和流式细胞术等体外实验检测肝癌细胞的功能，并通过裸鼠移植瘤模型和裸鼠肝转移模型检测lincSCRG 1-miR 26 a的体内作用。
结果
发现LincSCRG 1在人HCC组织和细胞系中强烈升高。miR 26 a和S期激酶相关蛋白2（SKP 2）分别被预测为lincSCRG 1的靶miRNA和miR 26 a的靶基因，具有直接结合位点。LincSCRG 1被证实是一种竞争性内源性RNA（ceRNA），通过在HCC细胞中对miR 26 a的负调节和对SKP 2的去抑制来实现。lincSCRG 1的过度表达（ov-lincSCRG 1）和miR 26 a的抑制（in-miR 26 a）能明显促进S期细胞的存活、集落形成、迁移和增殖，并能显著增加细胞周期蛋白D1、CDK 4、MMP 2/3/9、波形蛋白和N-钙粘蛋白的蛋白水平或抑制E-钙粘蛋白的蛋白水平，而lincSCRG 1的敲低（sh-lincSCRG 1）和miR 26 a的上调（mi-miR 26 a）对HCC细胞具有相反的作用。in-miR 26 a或SKP 2（ov-SKP 2）与sh-lincSCRG 1的共转染可以挽救sh-lincSCRG 1的抗癌功能，包括抑制HCC细胞的增殖和迁移。此外，sh-lincSCRG 1可有效抑制皮下移植瘤的生长和肺转移，而sh-lincSCRG 1的抗癌作用可被in-miR 26 a共转染逆转。
结论
LincSCRG 1作为miR 26 a的ceRNA限制其去抑制SKP 2的能力，从而在体外和体内诱导HCC细胞的增殖和迁移。lincSCRG 1的缺失可用作HCC的潜在治疗方法。
Background
Increasing evidence has demonstrated that long noncoding RNAs (lncRNAs) have regulatory functions in hepatocellular carcinoma (HCC). The link between lincSCRG1 and HCC remains unclear.
Methods
To explore the lincSCRG1 regulation axis, bioinformatics, RIP and luciferase reporter assay were performed. The expressions of lincSCRG1-miR26a-SKP2 were detected in HCC tissues and cell lines through qPCR and western blot. The functions of HCC cells were investigated through in vitro assays (MTT, colony formation, transwell and flow cytometry) and the inner effect of lincSCRG1-miR26a in vivo was evaluated by xenografts and liver metatstatic nude mice models.
Results
LincSCRG1 was found to be strongly elevated in human HCC tissues and cell lines. MiR26a and S phase kinase-related protein 2 (SKP2) were predicted as the target miRNA for lincSCRG1 and the target gene for miR26a with direct binding sites, respectively. LincSCRG1 was verified as a competing endogenous RNA (ceRNA) via negative regulation of miR26a and derepression of SKP2 in HCC cells. Both overexpression of lincSCRG1 (ov-lincSCRG1) and inhibition of miR26a (in-miR26a) obviously stimulated cellular viability, colony formation, migration and proliferation of S phase cells and also significantly increased the protein levels of cyclinD1, CDK4, MMP2/3/9, Vimentin, and N-cadherin or inhibited the protein level of E-cadherin of HCC cells, while knockdown of lincSCRG1 (sh-lincSCRG1) and upregulation of miR26a (mi-miR26a) had the opposite effects on HCC cells. Cotransfection of in-miR26a or overexpression of SKP2 (ov-SKP2) with sh-lincSCRG1 could rescue the anticancer functions of sh-lincSCRG1, including suppressing proliferation and migration of HCC cells. Additionally, sh-lincSCRG1 could effectively inhibit the growth of subcutaneous xenograft tumours and lung metastasis, while the anticancer effect of sh-lincSCRG1 could be reversed by cotransfection of in-miR26a.
Conclusions
LincSCRG1 acts as a ceRNA of miR26a to restrict its ability to derepress SKP2, thereby inducing the proliferation and migration of HCC cells in vitro and in vivo. Depletion of lincSCRG1 could be used as a potential therapeutic approach in HCC.
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