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Long Non‑Coding RNA H19 Regulates Viability and Metastasis, and Is Upregulated in Retinoblastoma

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Long Non‑Coding RNA H19 Regulates Viability and Metastasis, and Is Upregulated in Retinoblastoma 8424 ONCOLOGY LETTERS 15: 8424-8432, 2018 Long non‑coding RNA H19 regulates viability and metastasis, and is upregulated in retinoblastoma LI LI1, WEI CHEN1, YUCHUAN WANG1, LUOSHENG TANG2 and MEI HAN1 1Department of Vitreous and Retinal Diseases, Clinical College of Ophthalmology of Tianjin Medical University, Tianjin 300020; 2Department of Ophthalmology, The Second Affiliated Hospital of Xiangya Medical College, Central-South University, Changsha, Hunan 410083, P.R. China Received July 21, 2016; Accepted November 16, 2017 DOI: 10.3892/ol.2018.8385 Abstract. Retinoblastoma is the most common type of intra- an average incidence of between 1/15,000 and 1/20,000 live ocular pediatric malignant tumor, which typically affects births, typically arising in infants <6 years of age, often prior children <6 years of age. However, the underlying molecular to the age of 2 years (2). Advanced retinoblastoma is able to mechanisms of retinoblastoma progression remain unclear. The rapidly cover the eye, invade the optic nerve and eventually aim of the present study was to investigate the function of long spread to the central nervous system. Previous evidence from non-coding RNA (lncRNA) H19 in retinoblastoma clinical molecular, cellular and cytogenetic studies has indicated samples and cell lines, using reverse transcription-quantitative that retinoblastoma is typically caused by a mutation in the polymerase chain reaction, western blotting, colony formation, RB transcriptional co-repressor 1 (RB1) gene on chromo- MTT, fluorescence activated cell sorting, cell invasion and some 13 (3-5). RB1 inactivation results in mitotic defects, migration, and in vivo growth assays. The results demon- contributing to genomic instability, which manifests as aneu- strated that H19 may serve a critical oncogenic function in ploidy and chromosomal rearrangements (6,7). At present, the progression of retinoblastoma, as lncRNA H19 levels non-metastatic retinoblastoma is not considered a fatal were markedly increased in retinoblastoma cells and tissues childhood cancer and is effectively treated by enucleation, compared with corresponding controls. In addition, patients dependent on an early diagnosis and accurate prognosis of with retinoblastoma with increased lncRNA H19 expression the disease (8). Dalgard et al (9) observed that the retinoblas- experienced poorer survival time compared with those with toma cell lines Y79 and Weri-Rb1, and retinoblastoma tumor decreased lncRNA H19 levels. Knockdown of lncRNA H19 samples, presented with aberrant microRNA (miR)-34a and significantly suppressed retinoblastoma cell proliferation, miR-34b expression. In addition, this study provided indicated migration and invasion in vitro and in vivo. Furthermore, that knockdown of miR-34a may result in increased retino- lncRNA H19 expression was also associated with multiple blastoma cell proliferation and chemotherapeutic resistance. proteins, including cyclin-dependent kinase 1, B-cell The aim of the present study was to investigate long lymphoma-associated X protein, apoptosis regulator, tumor non-coding RNA (lncRNA) H19-mediated regulation of the protein p53, vimentin, cadherin 13 and matrix metallopepti- development of retinoblastoma in clinical samples and cell dase 9. In conclusion, lncRNA H19 may serve an important lines. LncRNAs are non-protein-coding transcripts, which function in tumorigenesis and may be a potential target for are >200 nucleotides in length, and regulate gene expression therapy and prognosis in retinoblastoma. transcriptionally or post-transcriptionally. These intergenic transcripts are involved in diverse cellular processes, including Introduction proliferation, migration, invasion, apoptosis and the repro- gramming of stem cell pluripotency (10-13). LncRNA H19 Retinoblastoma is a type of embryonic malignant tumor of has been considered as an oncogenic lncRNA in multiple the retina of the eye, which originates from primitive stem types of cancer, including hepatocellular, bladder carcinoma, cells (1). Retinoblastoma primarily occurs in childhood, with breast cancer, bladder tumor and glioma (14-17). Furthermore, previous studies reported that H19 regulates the development of gliomas via interactions with miR-675, which in addition contributes to the proliferation of gastric cancer cells and was associated with tumor metastasis (18-20). Emerging evidence Correspondence to: Dr Mei Han, Department of Vitreous and Retinal Diseases, Clinical College of Ophthalmology of Tianjin has also demonstrated that H19 expression is upregulated, and Medical University, 4 Gansu Road, Tianjin 300020, P.R. China is involved, in carcinogenesis and cancer metastasis via the E-mail: [email protected] promotion of cell cycle progression (21). However, the function of H19 in retinoblastoma remains unclear. Key words: long non-coding RNAs, H19, retinoblastoma In the present study, the clinical characteristics, biological function and potential underlying molecular mechanisms of lncRNA H19 in retinoblastoma were investigated. The LI et al: lncRNA H19 PROMOTES RETINOBLASTOMA 8425 results indicated that H19 levels were markedly increased Inc.), according to the manufacturer's protocol. RNA was in retinoblastoma cells and tissues. Furthermore, patients purified and then reverse-transcribed into cDNA using a with retinoblastoma with increased lncRNA H19 expression PrimeScript RT Reagent kit (Takara Biotechnology Co., Ltd., experienced poorer survival time compared with patients Dalian, China) according to the manufacturer's protocol. with lower levels of lncRNA H19 expression. Furthermore, qPCR was performed using SYBR Premix Ex Taq (Takara lncRNA H19 expression was also associated with several Biotechnology Co., Ltd.), according to the manufacturer's proteins, including cyclin-dependent kinase 1 (CDK1), protocol, and run on an ABI Prism 7000 Sequence Detection B-cell lymphoma 2-associated X, apoptosis regulator (Bax), System. Relative expression of lncRNA H19 (primer: Forward, tumor protein p53 (p53), vimentin, cadherin 13 (CDH13) and 5'-ATC GGT GCC TCA GCG TTC GG-3'; and reverse, 5'-CTG matrix metalloproteinase 9 (MMP9). The oncogenic function TCC TCG CCG TCA CAC CG-3) was normalized to the expres- of H19 suggests that it may serve as a potential target for sion of GAPDH (primer: Forward, 5'-AGC CAC ATC GCT CAG retinoblastoma therapy and prognostic prediction. ACA C-3' and reverse, 5'-GCC CAA TAC GAC CAA ATC C-3'). Relative gene expression levels were quantified using the 2-ΔΔCq Materials and methods method (22). The thermocycling conditions for lncRNA H19 quantification were as follows: 95˚C for 10 min; 40 cycles of Cell lines and tumor tissues. The present study was approved 95˚C for 15 sec and 60˚C for 1 min. Each sample was examined by the Research Ethics Committee of Tianjin Eye Hospital in triplicate. (Tianjin, China). Written informed consent for all biological procedures was obtained from each patient, or their parents, Small interfering (si)RNA transfection. RNA interference was and specimens for the present study were anonymized. Patients conducted using synthetic siRNA duplexes. Two synthetic who had received treatment prior to surgery were excluded from siRNA duplexes (si-H19) corresponding to the H19 mRNA the present study. The tumor samples were collected between sequences, 5'-CCC ACA ACA UGA AAG AAA U-3' (forward) June 2011 until November 2015 and were extracted from and 5'-GCU AGA GGA ACC AGA CCU U-3' (reverse), were enucleated eyes and immediately snap-frozen in liquid used to inhibit H19 RNA expression. si-H19 and si-negative nitrogen and stored at ‑80˚C. A total of 80 freshly frozen reti- control (NC) were purchased from Guangzhou RiboBio noblastoma tissue samples (44 males and 36 females; the age Co., Ltd. (Guangzhou, China). Cells were cultured in 6-well distribution: 40 patients ≥2 years and 40 patients <2 years), plates and maintained until they reached ~60% confluence, and five normal retina samples (3 males and 2 females; the prior to transfection with siRNA duplexes (25 nM) using age distribution: 2 patients ≥2 years and 3 patients <2 years) Lipofectamine® 2000 (Invitrogen; Thermo Fisher Scientific, obtained from ruptured globes, were collected at Tianjin Eye Inc.), according to the manufacturer's protocol. Transfection Hospital (Tianjin, China). efficiency to assess the inhibition ofH19 after 48 h of transfec- tion in Y79 cells was performed using RT-qPCR as previously Cell culture. The cell lines used in the present study were outlined. purchased from the Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences (Shanghai, China). The Flow cytometric analysis. Cell apoptosis was examined human retinal pigment epithelial cell line ARPE-19 was by flow cytometry. Weri‑Rb1 or Y79 cells were seeded at a cultured in Dulbecco's modified Eagle's medium (Gibco; density of 1x104 cells/well in 96-well plates. In brief, cells Thermo Fisher Scientific, Inc., Waltham, MA, USA) supple- were transfected with si-H19 or si-NC as aforementioned mented with 10% fetal bovine serum (FBS; Gibco; Thermo and, 2 days post-transfection, cells were trypsinized by 0.25% Fisher Scientific, Inc.), 100 U/ml penicillin (Invitrogen, Trypsin (Gibco; Thermo Fisher Scientific, Inc.), followed by Thermo Fisher Scientific, Inc.), and 100 mg/ml streptomycin centrifugation at 350 x g for 2 min. and washed with PBS. (Invitrogen, Thermo Fisher Scientific, Inc.). The human retinal Cells were then resuspended in PBS and fixed with 100% microvascular endothelial cell
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