The HNF1α-regulated lncRNA HNF1A-AS1 reverses the malignancy of hepatocellular carcinoma by enhancing the phosphatase activity of SHP-1

• DOI: 10.1186/s12943-018-0813-1
• Publication Date: 2018-02-21T11:47:06Z
• Authors: Chen-Hong Ding; Chuan Yin; Shi-Jie Chen; Liang-Zhi Wen; Kai Ding; Shu-Juan Lei; Jin-Pei Liu; Jian Wang; Kai-xian Chen; Hua-liang Jiang; Xin Zhang; Cheng Luo; Wei-Fen Xie
• Keywords: Male; 0301 basic medicine; Carcinoma, Hepatocellular; Models, Biological; Mice; 03 medical and health sciences; Genes, Reporter; Cell Line, Tumor; Animals; Humans; Hepatocyte Nuclear Factor 1-alpha; Neoplasm Metastasis; RC254-282; Base Sequence; Research; Gene Expression Profiling; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Liver Neoplasms; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; 3. Good health; HNF1A-AS1; Enzyme Activation; Gene Expression Regulation, Neoplastic; Disease Models, Animal; Cell Transformation, Neoplastic; Hepatocellular carcinoma, SHP-1, phosphatase activity; RNA, Long Noncoding; HNF1α; Protein Binding

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.