MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway.
MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway.
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MicroRNA-1296 通过靶向 SRPK1 介导的 PI3K/AKT 通路抑制肝细胞癌的转移和上皮间质转化。
DOI：
10.1186/s12943-017-0675-y
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发表时间：
2017-06-12
期刊：
影响因子：
37.3
通讯作者：
Tu K
中科院分区：
文献类型：
--
作者：
Xu Q;Liu X;Liu Z;Zhou Z;Wang Y;Tu J;Li L;Bao H;Yang L;Tu K
背景越来越多的证据表明，miRNAs参与了肝细胞癌（HCC）的发生、发展.最近报道miR-1296的低表达促进人类癌症的生长和转移。方法采用qRT-PCR方法检测miR-1296在HCC组织和细胞中的表达水平，并对miR-1296在HCC中的作用进行研究。免疫印迹和免疫荧光法用于检测HCC细胞中上皮向间质转化（EMT）的进展。进行Transwell测定以确定HCC细胞的迁移和侵袭。采用小鼠肺转移模型评价肝癌的体内转移情况。结果发现miR-1296在肝癌组织和细胞系中的表达降低，且与肝癌的转移和复发相关。值得注意的是，miR-1296过表达抑制HCCLM 3细胞的迁移、侵袭和EMT进展，而miR-1296缺失促进Hep 3B细胞在体外和体内的这些生物学行为。此外，miR-1296通过直接结合SRPK 1的3′-UTR来反向调节SRPK 1的丰度，这随后导致p-AKT的抑制。SRPK 1的再表达或PI 3 K/AKT通路的激活至少部分地消除了miR-1296对HCC细胞迁移、侵袭和EMT进展的影响。此外，miR-1296和SRPK 1的表达与HCC患者的不良临床特征和不良预后显著相关。我们发现缺氧是HCC中miR-1296低表达的原因。miR-1296可逆转低氧对肝癌细胞转移和EMT的促进作用。结论miR-1296低表达可作为肝癌预后的生物标志物。缺氧诱导的miR-1296缺失可能通过靶向SRPK 1/AKT通路促进肝癌细胞的转移和EMT。
BackgroundIncreasing evidences demonstrate that miRNAs contribute to development and progression of hepatocellular carcinoma (HCC). Underexpression of miR-1296 is recently reported to promote growth and metastasis of human cancers. However, the expression and role of miR-1296 in HCC remain unknown.MethodsThe levels of miR-1296 in HCC tissues and cells were detected by qRT-PCR. Immunoblotting and immunofluorescence were used for detection of epithelial-to-mesenchymal transition (EMT) progression in HCC cells. Transwell assays were performed to determine migration and invasion of HCC cells. A lung metastasis mouse model was used to evaluated metastasis of HCC in vivo. The putative targets of miR-1296 were disclosed by public databases and a dual-luciferase reporter assay.ResultsWe found that the expression of miR-1296 was reduced in HCC tissues and cell lines, and it was associated with metastasis and recurrence of HCC. Notably, miR-1296 overexpression inhibited migration, invasion and EMT progress of HCCLM3 cells, while miR-1296 loss facilitated these biological behaviors of Hep3B cells in vitro and in vivo. In addition, miR-1296 inversely regulated SRPK1 abundance by directly binding to its 3′-UTR, which subsequently resulted in suppression of p-AKT. Either SRPK1 re-expression or PI3K/AKT pathway activation, at least partially, abolished the effects of miR-1296 on migration, invasion and EMT progress of HCC cells. Furthermore, miR-1296 and SRPK1 expression were markedly correlated with adverse clinical features and poor prognosis of HCC patients. We showed that hypoxia was responsible for the underexpression of miR-1296 in HCC. And the promoting effects of hypoxia on metastasis and EMT of HCC cells were reversed by miR-1296.ConclusionsUnderexpression of miR-1296 potentially serves as a prognostic biomarker in HCC. Hypoxia-induced miR-1296 loss promotes metastasis and EMT of HCC cells probably by targeting SRPK1/AKT pathway.