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HOTAIR, a Long Non‑Coding RNA Driver of Malignancy Whose Expression Is Activated by FOXC1, Negatively Regulates Mirna‑1 in Hepatocellular Carcinoma

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HOTAIR, a Long Non‑Coding RNA Driver of Malignancy Whose Expression Is Activated by FOXC1, Negatively Regulates Mirna‑1 in Hepatocellular Carcinoma ONCOLOGY LETTERS 12: 4061-4067, 2016 HOTAIR, a long non‑coding RNA driver of malignancy whose expression is activated by FOXC1, negatively regulates miRNA‑1 in hepatocellular carcinoma DONG-NA SU1, SHI-PIN WU1, HONG-TAO CHEN1 and JIN-HUA HE2 1Department of Infectious Diseases, Shenzhen People's Hospital, The Second Affiliated Hospital of Jinan University, Shenzhen, Guangdong 518020; 2Department of Laboratory, Panyu Central Hospital, Guangzhou, Guangdong 511400, P.R. China Received May 23, 2015; Accepted August 12, 2016 DOI: 10.3892/ol.2016.5127 Abstract. Evidence is rapidly accumulating that long The interaction between miR-1 and HOTAIR was examined non-coding RNAs (lncRNAs) are involved in human using a luciferase reporter assay. Gain and loss of function tumorigenesis and are dysregulated in multiple cancers, approaches were used to determine the changes of HOTAIR or including hepatocellular carcinoma (HCC). lncRNAs can miR-1 expression. The relative levels of FOXC1 and HOTAIR regulate essential pathways that contribute to tumor initia- expression in HCC tissues and HepG2 cells were significantly tion and progression with tissue specificity, which suggests higher than those in normal liver LO2 cells and adjacent carci- that lncRNAs may be valuable biomarkers and therapeutic noma tissues; the relative expression of miR-1 exhibited the targets. HOX transcript antisense intergenic RNA (HOTAIR) opposite pattern. Overexpression of HOTAIR promoted HCC has previously been demonstrated to be an oncogene and a cell proliferation and progression of tumor xenografts. The negative prognostic factor in a variety of cancers; however, the present authors have demonstrated that FOXC1 binds to the factors that contribute to the upregulation of HOTAIR and the upstream region of HOTAIR in HCC cells and that FOXC1 interaction between HOTAIR and microRNAs (miRNAs or activates lncRNA HOTAIR expression in HCC HepG2 cells, miRs) are largely unknown. In the present study, the expression which suggests that HOTAIR harbors a miRNA-1 binding site. levels of HOTAIR, forkhead box C1 (FOXC1) and miRNA-1 The present data revealed that this binding site is vital for the were examined in 50 matched pairs of HCC and HCC cells. regulation of miRNA-1 by HOTAIR. Furthermore, HOTAIR The effects of HOTAIR on HCC cell proliferation were tested negatively regulated the expression of miRNA-1 in HepG2 using trypan blue exclusion assay. The effect of HOTAIR cells. Additionally, the present study demonstrated that the on HCC growth in vivo was determined in a (nu/nu) mouse oncogenic activity of HOTAIR is in part based on the negative model. A computational screening of HOTAIR promoter was regulation of miR-1. Taken together, these results suggest that conducted to search for transcription factor-binding sites. HOTAIR is a FOXC1-activated driver of malignancy, which FOXC1 binding to the promoter region of HOTAIR was acts in part through the repression of miR-1. confirmed using a chromatin immunoprecipitation assay. A search for miRNAs that had complementary base paring with Introduction HOTAIR was performed utilizing an online software program. Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortalities, with nearly 600,000 mortali- ties occurring worldwide each year (1). Although resection is Correspondence to: Dr Shi-Pin Wu, Department of Infectious considered a potentially curative treatment for HCC patients, Diseases, Shenzhen People's Hospital, The Second Affiliated the 1-year post-operative survival rate is only 30-40% (2). Hospital of Jinan University, 1017 Dong Men Bei Lu, Luo Hu, Thus, it is necessary to improve our understanding of Shenzhen, Guangdong 518020, P.R. China the disease-causing mechanisms and to identify specific E-mail: [email protected] biomarkers for HCC progression to aid in the prediction and improvement in clinical outcomes. Abbreviations: lncRNA, long non-coding RNA; miR, microRNA; siRNA, small interfering RNA; TF, transcription factor; RT-qPCR, Non-coding RNAs (ncRNAs) are subdivided into reverse transcription-quantitative polymerase chain reaction; HCC, two groups: Small ncRNAs (<200 nt) and long ncRNAs hepatocellular carcinoma; HOTAIR, HOX transcript antisense (lncRNAs) (3,4). Small ncRNAs, including the well-documented intergenic RNA; FOXC1, forkhead box C1 microRNAs (miRNAs or miRs), have received great attention, since they are important in cancer (5). It has been proposed that Key words: long non-coding RNA, HOTAIR, miR-1, FOXC1, lncRNAs are involved in the epigenetic regulation of coding hepatocellular carcinoma genes, and thus, exert a powerful effect on a number of physio- logical and pathological processes, including the pathogenesis of numerous human cancers (6). It has been reported that 4062 SU et al: FOXC1-ACTIVATED HOTAIR NEGATIVELY REGULATES miRNA-1 lncRNA HOX transcript antisense intergenic RNA (HOTAIR) sequence (5'-UGG AAU GUA AAG AAG UAU GUAU-3') is expression is significantly higher in HCC tissues than in adja- available from the miR registry (MIMAT000416; http://www. cent non-cancerous tissues (7). Patients with HCC tumors that mirbase.org/cgi-bin/mirna_entry.pl?acc=MIMAT0000416). To overexpress HOTAIR have an increased risk of HCC recurrence prevent the formation of a termination signal, TTG GCC ACT following hepatectomy, and there is also a correlation between GACT was selected as the region in a miR expression vector HOTAIR overexpression and increased risk of lymph node template (pcDNA3.1; Invitrogen; Thermo Fisher Scientific, Inc., metastasis (8). The overexpression of HOTAIR is an indepen- Waltham, MA, USA). The sequence TGCT was added to the dent prognostic factor for HCC recurrence in liver transplant 5' sense strand template of the miR expression vector, while patients (9). Furthermore, patients with high tumor expression of GTCC was added to the 5' antisense strand template (17). In HOTAIR have a significantly shorter recurrence-free survival addition, a non-specific sequence was designed and synthesized than patients with low expression of HOTAIR (10). by Shanghai GenePharma Co., Ltd. The eukaryotic expression The mechanism by which HOTAIR exerts its oncogenic vector plasmid targeting hsa-miR-1 was designated pmiR-1. activity remains largely unknown. A regulatory mechanism The sequence of FOXC1 was synthesized and sub-cloned has been proposed in which RNAs cross-talk via competing into pcDNA3.1 (Invitrogen; Thermo Fisher Scientific, Inc.) to shared miRs (11). In addition, lncRNAs directly interact with generate pFOXC1. Empty pcDNA3.1 vector was used as a nega- RNA-binding proteins and localize to the gene promoter region tive control (NC). to regulate gene expression (12). The proposed competitive endogenous RNAs (ceRNAs) mediate the bioavailability of Cell culture. HCC HepG2 and LO2 cells were purchased from miRs on their targets, thus imposing another level of post-tran- the Shanghai Institute of Cell Biology (Shanghai, China). The scriptional regulation (13). An example of this type of regulation cell lines were cultured in Dulbecco's modified Eagle's medium is the lncRNA colon cancer associated transcript 1, (CCAT1), (Gibco; Thermo Fisher Scientific, Inc.) containing 10% fetal which binds miR-218-5p and forms a regulatory interaction (14). bovine serum (HyClone; GE Healthcare Life Sciences, Logan, Using jaspar bioinformatics software (http://jaspar.genereg. UT, USA), 100 U/ml penicillin and 100 µg/ml streptomycin net), forkhead box C1 (FOXC1) shared binding sites with the (Invitrogen; Thermo Fisher Scientific, Inc.). Cells were main- upstream promoter region of HOTAIR were predicted. Further- tained in a humidified incubator at 37˚C in the presence of 5% more, miR-1 was identified as the miR that shares binding sites CO2. All cell lines were passaged for <6 months. with HOTAIR using starBase 2.0 (http://starbase.sysu.edu.cn). Thus, the present authors hypothesized that transcription factors Cell transfection. All plasmid vectors (pmiR-1, pFOXC1 and (TFs) activate the transcription of HOTAIR. Furthermore, empty vector) used for cell transfection were extracted using HOTAIR overexpression inhibits the expression of miR-1. This Hieff Trans™ Liposomal Transfection Reagent (Yeasen Biotech- hypothesis is discussed to better elucidate the pathogenesis of nology Co., Ltd., Shanghai, China). HepG2 cells cultured on HCC. 6-well plates were transfected with pmiR-1, pFOXC1 or empty vector using Lipofectamine 2000 (Invitrogen; Thermo Fisher Materials and methods Scientific, Inc.) according to the manufacturer's protocol. Cells were harvested after 48 h for quantitative polymerase chain reac- Tissue specimens. Fresh-frozen and paraffin-embedded HCC tion (qPCR). Methods for transfecting cells with LV3-HOTAIR tissues and corresponding adjacent non-tumorous gastric were adopted, as previously described (17). Small interfering samples were obtained from Chinese patients at Shenzhen RNAs (siRNAs) were designed and synthesized by Shanghai People's Hospital (Shenzhen, China) between January 2010 GenePharma Co., Ltd. The siRNA sequence used in the present and December 2014. All cases were reviewed by a pathologist study was as follows: Sense, 5'-GGG AGA TGT TCG AGT and histologically confirmed as HCC. Informed consent was CAC AGA-3' and antisense, 5'-GCG TAA AGC TCG GGT AAG obtained from all patients and the study was approved by the TAG-3'. The siRNAs sequences targeting human HOTAIR were Institutional Ethics Committee of Shenzhen People's Hospital. as follows: Sense, 5'-GGA GAA CAC UUA AAU
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