MicroRNA-486-5p, which is downregulated in hepatocellular carcinoma, suppresses tumor growth by targeting PIK3R1
MicroRNA-486-5p, which is downregulated in hepatocellular carcinoma, suppresses tumor growth by targeting PIK3R1
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DOI：
10.1111/febs.13167
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发表时间：
2015-02-01
期刊：
影响因子：
5.4
通讯作者：
Luo, Xiao-Ling
中科院分区：
文献类型：
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作者：
Huang, Xin-Ping;Hou, Jin;Luo, Xiao-Ling
失调的microRNA及其在肿瘤发生和发展中的作用引起了广泛关注。在我们实验室进行的先前研究中，Illumina Solexa对非肿瘤和肝细胞癌（HCC）组织中的miRNomes进行了大规模平行签名测序，结果显示miR-486- 5 p在HCC中显著下调，但其在HCC发展中的作用仍然未知。在这项研究中，miR-486- 5 p在HCC组织和匹配的对照组织中，以及在7个HCC细胞系（QGY-7701、QGY-7703、QGY-7404、SMMC-7721、Huh 7、HepG 2和PCL/PRF/5）和人正常肝细胞（HL-7702）中的水平通过实时定量RT-PCR进行检测。我们发现miR-486- 5 p在HCC组织和所有7种HCC细胞系中的水平显著降低。miR-486- 5 p过表达可显著抑制肝癌细胞的增殖、迁移和侵袭，并抑制肝癌细胞在体内的生长。从机制上讲，通过双荧光素酶报告基因测定和实时定量RT-PCR和蛋白质印迹分析，证实miR-486- 5 p直接靶向PIK 3R 1表达，从而抑制磷脂酰肌醇3-激酶-AKT途径活化。此外，PIK 3R 1敲低通过抑制HCC生长、迁移和侵袭来模拟miR-486- 5 p过表达的作用。此外，相关性分析、Kaplan-Meier估计和考克斯比例风险模型显示，miR-486 - 5 p表达较低的患者中，miR-486- 5 p和PIK 3 R1之间呈负相关，HCC切除术后复发时间较短。因此，我们得出结论，在肝癌中经常下调的miR-486- 5 p通过靶向PIK 3R 1和磷脂酰肌醇3-激酶-AKT激活来抑制肝癌进展。数据库Solexa测序数据可在GEO数据库（www.ncbi.nlm.nih.gov/geo/）中获得，登录号为GSE 21279。
Deregulated microRNAs and their roles in carcinogenesis and cancer progression have attracted much attention. In previous studies conducted in our laboratory, the Illumina Solexa massively parallel signature sequencing of miRNomes in nontumor and hepatocellular carcinoma (HCC) tissues revealed that miR-486-5p was significantly downregulated in HCC, but its role in HCC development remains unknown. In this study, miR-486-5p levels in HCC tissues and matched control tissues, and in seven HCC cell lines (QGY-7701, QGY-7703, QGY-7404, SMMC-7721, Huh7, HepG2, and PCL/PRF/5) and human normal liver cells (HL-7702), were tested by real-time quantitative RT-PCR. We found that the level of miR-486-5p was significantly decreased in HCC tissue and in all seven HCC cell lines. Overexpression of miR-486-5p markedly suppressed HCC cell proliferation, migration and invasion invitro, and inhibited HCC growth invivo. Mechanistically, miR-486-5p was confirmed to directly target PIK3R1 expression, thereby suppressing phosphatidylinositol 3-kinase-AKT pathway activation, by dual luciferase reporter assay and real-time quantitative RT-PCR and western blot analysis. In addition, PIK3R1 knockdown mimicked the effects of miR-486-5p overexpression by inhibiting HCC growth, migration, and invasion. Furthermore, correlation analysis, Kaplan-Meier estimates and Cox proportional hazard models showed an inverse correlation between miR-486-5p and PIK3R1, as well as a shorter time to recurrence after HCC resection, in patients with lower miR-486-5p expression. Hence, we conclude that miR-486-5p, which is frequently downregulated in HCC, inhibits HCC progression by targeting PIK3R1 and phosphatidylinositol 3-kinase-AKT activation.DatabaseThe Solexa sequencing data are available in GEO database (www.ncbi.nlm.nih.gov/geo/) under accession number GSE21279..