The HNF1α-regulated lncRNA HNF1A-AS1 reverses the malignancy of hepatocellular carcinoma by enhancing the phosphatase activity of SHP-1.
The HNF1α-regulated lncRNA HNF1A-AS1 reverses the malignancy of hepatocellular carcinoma by enhancing the phosphatase activity of SHP-1.
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HNF1α调控的lncRNA HNF1A-AS1通过增强SHP-1的磷酸酶活性逆转肝细胞癌的恶性程度
DOI：
10.1186/s12943-018-0813-1
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发表时间：
2018-02-21
期刊：
影响因子：
37.3
通讯作者：
Xie WF
中科院分区：
文献类型：
--
作者：
Ding CH;Yin C;Chen SJ;Wen LZ;Ding K;Lei SJ;Liu JP;Wang J;Chen KX;Jiang HL;Zhang X;Luo C;Xie WF
我们的前期研究表明，肝细胞核因子1α（hepatocyte nuclear factor 1α，HNF 1 α）对肝细胞癌（hepatocellular carcinoma，HCC）有较强的治疗作用。然而，HNF 1 α逆转HCC恶性的分子机制需要进一步阐明。用lncRNA芯片鉴定HNF 1 α调控的长链非编码RNA（lncRNA）。应用染色质免疫沉淀和荧光素酶报告基因技术研究HNF 1 α对HNF 1A反义RNA 1（HNF 1A-AS 1）的转录调控机制。在体外和体内评价HNF 1A-AS 1对HCC恶性肿瘤的作用。采用RNA pulldown、RNA结合蛋白免疫沉淀和生物层干涉法验证HNF 1A-AS 1与含Src同源区2结构域的磷酸酶1（SHP-1）的相互作用。HNF 1 α调节肝癌细胞中一组lncRNA的表达。其中HNF 1A-AS 1在肝癌细胞和肝癌组织中的表达水平与HNF 1 α的表达水平显著相关。HNF 1 α通过直接与HNF 1A-AS 1的启动子区结合而激活其转录。HNF 1A-AS 1在体内外均能抑制肝癌细胞的生长和转移。HNF 1A-AS 1基因的敲除可逆转HNF 1 α对肝癌细胞迁移和侵袭的抑制作用。重要的是，HNF 1A-AS 1以高结合亲和力（KD = 59.57 ± 14.29 nM）直接结合SHP-1的C末端，并增加SHP-1的磷酸酶活性。SHP-1酶活性的抑制基本上逆转了HNF 1 α或HNF 1A-AS 1诱导的HCC细胞转移特性的降低。结果表明，HNF 1A-AS 1是HNF 1 α在肝癌细胞中的直接反式激活靶点，参与了HNF 1 α的抗肝癌作用。HNF 1A-AS 1通过与SHP-1的直接相互作用作为磷酸酶激活剂发挥作用。这些发现表明，HNF 1 α/HNF 1A-AS 1/SHP-1轴的调节可能在HCC的治疗中具有有益的作用。本文的在线版本（10.1186/s12943-018-0813-1）包含补充材料，可供授权用户使用。
Our previous study has demonstrated that hepatocyte nuclear factor 1α (HNF1α) exerts potent therapeutic effects on hepatocellular carcinoma (HCC). However, the molecular mechanisms by which HNF1α reverses HCC malignancy need to be further elucidated. lncRNA microarray was performed to identify the long noncoding RNAs (lncRNAs) regulated by HNF1α. Chromatin immunoprecipitation and luciferase reporter assays were applied to clarify the mechanism of the transcriptional regulation of HNF1α to HNF1A antisense RNA 1 (HNF1A-AS1). The effect of HNF1A-AS1 on HCC malignancy was evaluated in vitro and in vivo. RNA pulldown, RNA-binding protein immunoprecipitation and the Bio-Layer Interferometry assay were used to validate the interaction of HNF1A-AS1 and Src homology region 2 domain-containing phosphatase 1 (SHP-1). HNF1α regulated the expression of a subset of lncRNAs in HCC cells. Among these lncRNAs, the expression levels of HNF1A-AS1 were notably correlated with HNF1α levels in HCC cells and human HCC tissues. HNF1α activated the transcription of HNF1A-AS1 by directly binding to its promoter region. HNF1A-AS1 inhibited the growth and the metastasis of HCC cells in vitro and in vivo. Moreover, knockdown of HNF1A-AS1 reversed the suppressive effects of HNF1α on the migration and invasion of HCC cells. Importantly, HNF1A-AS1 directly bound to the C-terminal of SHP-1 with a high binding affinity (KD = 59.57 ± 14.29 nM) and increased the phosphatase activity of SHP-1. Inhibition of SHP-1 enzymatic activity substantially reversed the HNF1α- or HNF1A-AS1-induced reduction on the metastatic property of HCC cells. Our data revealed that HNF1A-AS1 is a direct transactivation target of HNF1α in HCC cells and involved in the anti-HCC effect of HNF1α. HNF1A-AS1 functions as phosphatase activator through the direct interaction with SHP-1. These findings suggest that regulation of the HNF1α/HNF1A-AS1/SHP-1 axis may have beneficial effects in the treatment of HCC. The online version of this article (10.1186/s12943-018-0813-1) contains supplementary material, which is available to authorized users.
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3.2
作者：
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