Home Medicine LncRNA TUG1 is upregulated and promotes cell proliferation in osteosarcoma
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LncRNA TUG1 is upregulated and promotes cell proliferation in osteosarcoma

  • Feng Yun-Bo EMAIL logo , Liu Xiao-Po , Li Xiao-Li , Cao Guo-Long , Zhang Pei and Tian Fa-Ming
Published/Copyright: May 30, 2016
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Open Medicine
From the journal Open Medicine Volume 11 Issue 1

Abstract

Objective: To examine the expression and function of long non-coding RNA taurine up-regulated 1 (TUG1) in human osteosarcoma cells. Methods: Real-time quantitive PCR was used to detect the transcription level of TUG1 in a series of osteosarcoma cell lines. Knockdown of TUG1 in U2OS cells was carried out by transient transfection of siRNAs. MTT assay was performed to access the cell growth rates. Afterwards, RNA and protein of these cells were extracted to analyze the transfection efficient as well as the expression of other molecules. Results: Compared to the normal cell line, TUG1 exhibited a significant upregulation in osteosarcoma cells. Phenotyping analysis showed the growth-promotion activity of TUG1, since knockdown of TUG1 resulted in declined proliferation. We also found that AKT phosphorylation was impaired after TUG1 was inhibited, suggesting that the AKT pathway was involved in the regulation of TUG1 in U2OS cells. Conclusion: Our data provided evidence that TUG1 was upregulated and acted as a possible oncogene via positively regulating cell proliferation in osteosarcoma cells.

Key words: TUG1; osteosarcoma; proliferation; AKT

1 Introduction

Long non-coding RNA (LncRNA) is a group of transcribed non-coding RNAs that contain more than 200 nt in length and not encoding any proteins [1,2]. They constitute a major but still poorly characterized part of human transcriptome. They were initially considered as genomic noise. Thanks to the highly thorough sequencing as well as functional technologies in recent years, lncRNAs have been demonstrated to play important roles in basic biological processes [3-5], like DNA replication, gene transcription and epigenetic modification. Recently, we gradually recognized that lncRNAs were closely correlated with human carcinogenesis since they had been proved to be abnormally expressed and act as either oncogenes or tumor suppressors [6-9]. In addition, it is a hot topic to discuss the clinical application of specific lncRNAs as a potential novel class of biomarkers for cancer diagnosis and prognosis [10-12].

Taurine up-regulated 1 (TUG1), a 7.1-kb lncRNA, was a long non-coding RNA that was characterized first two years ago in a paper exploring differential expression of lncRNAs in DNA damage-induced cell death in Hela cells [13]. In the following studies, it was clear that TUG1 was increased in bladder urothelial carcinomas, and promote cell proliferation and apoptosis-inhibition [14]. It exhibited similar high expression and pro-tumorous effects in esophageal squamous cell carcinoma, in which TUG1 had the ability to promote cell migration [15]. However, in other types of cancers, including non-small cell lung cancer [16], TUG1 was reported to be downregulated and inhibits cell proliferation as well as inducing apoptosis. This cancer type-specific activity of TUG1 illustrated the importance of the microenvironment. Although it was already found that in osteosarcoma TUG1 was upregulated [17], the related mechanisms were still lacking. In our study, experiments were designed to access its expression, function and possible signaling pathway that TUG1 regulated.

2 Materials and Methods

2.1 Cell Culture

Human normal osteoblastic cell line hFOB1.19 and human Human normal osteoblastic cell line hFOB1.19 and human osteosarcoma cell line SaoS2, MG63, U2OS and HOS were ordered from the Cell Line Resource Center, Shanghai Institutes for Biological Sciences, the Chinese Academy of Sciences (Shanghai, China) or ATCC (American Type Culture Collection, USA). All these cells lines were cultured in 1640 or DMEM supplemented with 10% fetal bovine serum, penicillin (100units/ml) and streptomycin (100μg/ml) at 37°C in a humidified 5% CO2 atmosphere.

2.2 Reagents and Antibodies

Both the control siRNA and LncRNA TUG1 siRNA were purchased by GenePharma (Shanghai, China). The cells were transfected with mimics or inhibitors using Lipofectamine RNAiMAX as described below. PCNA and β-actin antibodies were purchased from Santa Cruz Biotechnology Inc. Phosphated-Akt and total-Akt antibodies were purchased from Cell Signaling Technology Inc. Phosphated-Akt and total-Akt antibodies were purchased from Cell Signaling Technology Inc.

2.3 Transient Transfection

Transfections were performed using Lipofectamine RNAiMAX Reagent (Invitrogene) as per the manufacturer’s instructions. After 48 hours, cells were harvest for the other experiments.

2.4 Real-Time PCR Analysis

Total RNAs was extracted by TRIZOL from the cell lines of human osteosarcoma. Real-time PCRs were performed using an ABI7900 real-time PCR system (Applied Biosystems, Carlsbad, CA) and the SYBR Premix Ex Taq reagent kit (Takara Bio Inc., Shiga, Japan) using Ct quantization method. Ct value was the number of PCR cycles at which the fluorescence signal exceeded the threshold. ∆Ct was the difference in Ct values between the control (GAPDH) and test targets (LncRNA TUG1). ∆∆Ct was the difference in ∆Ct values between the experimental group and paired control group, which represents the fold change in long non-coding RNA expression. The primers change in long non-coding RNA expression. The primers were designed by Primer premier 5.0, and the sequences were as follows:

TUG1

Forward 5’-CTGAAGAAAGGCAA CATC-3’;

Reverse 5’-GTAGGCTACTACAGGATTTG-3’;

GAPDH

Forward 5’-GTCAACGGATTTGGTCTGTATT-3’;

Reverse 5’-AGTCTTCTGGGTGGCAGTGAT-3’.

2.5 Western Blot

For western blot analysis, in brief, the cell lysate was run on SDS-PAGE in 9% acrylamide gels and transferred onto nitrocellulose membranes. After blocking, blots were incubated with mAb. β-actin was used to normalise protein loading. A total of 30μg of cell lysate was loaded in each lane for western blot analysis.

2.6 MTT Assay

Cellular growth ability was determined by the MTT assay. In brief, 3×103 U2OS cells/well were plated into 96-well plates. At the indicated time point, 5μl MTT solution (5mg/ ml) was added into each well and incubated for 2h at room temperature (RT). Then the reaction was terminated by 100μl DMSO and the absorbance at 590nm was measured on a microplate-reader.

2.7 Statistic Analysis

Data are presented as mean ± sd of at least triplicate experiments. Statistical analyses were performed by using SPSS version 18.0 (SPSS, Chicago, IL) and GraphPad Prism Software (GraphPad Software, Inc., San Diego, CA). For all statistical analyses, a P value of < 0.05 was considered statistically significant.

3 Results

Increased expression of TUG1 in osteosarcoma cell lines

Firstly, we applied real-time PCR to quantify the expression of TUG1 in osteosarcoma cell lines. As shown in Figure 1A, when compared to the normal hFOB1.19 cell line, the expression of TUG1 was significantly upregulated in a panel of osteosarcoma cells, including SaoS2, MG63, U2OS and HOS cell lines. This finding was consistent with the previous conclusion that supported its upregulation in clinical osteosarcoma tissue samples [17].

Figure 1 LncRNA TUG1 is upregulated in osteosarcoma cell line. QRT-PCR analysis performed to detect expression of LncRNA TUG1 expression in human normal osteoblastic cell line hF081.19 and human osteosarcoma cell lines. LncRNA TUG1 expression levels were calculated by the 2-∆CT method and normalized to GAPDH. ∆Ct is the difference in Ct values between LncRNA and GAPDH. The plot shows the TUG1 expression was elevated.
Figure 1

LncRNA TUG1 is upregulated in osteosarcoma cell line. QRT-PCR analysis performed to detect expression of LncRNA TUG1 expression in human normal osteoblastic cell line hF081.19 and human osteosarcoma cell lines. LncRNA TUG1 expression levels were calculated by the 2-∆CT method and normalized to GAPDH. ∆Ct is the difference in Ct values between LncRNA and GAPDH. The plot shows the TUG1 expression was elevated.

3.1 TUG1 has a growth-promotion activity in osteosarcoma

Afterwards, TUG1 siRNA was designed and transiently transfected into the U2OS cells to knockdown the endogenous expression of TUG1. The knockdown efficiency was revealed to be effective, as approximately 80% of TUG1 expression was knockdown (Figure 2A). The MTT assay was performed to visualize the proliferation of cells. As shown in Figure 2B, after TUG1 was inhibited, the growth rate of U2OS cells had decreased compared with the cells in the control group. These results confirmed the previous conclusion that regards TUG1 as a potential oncogene via regulating cell proliferation.

Figure 2 TUG1 promotes tumor proliferation in U2OS cells. (A) U2OS cells were transfected with control siRNA or lncRNA TUG1 siRNA. In 48h, the cells were harvested for examining knockdown effect. (B) U2OS cells were transfected with control siRNA or lncRNA TUG1 siRNA. In 24h, cells were trypsinized and seeded into four 96-well plates at a density of 3×103 cells for MTT assay as described under Materials and Methods. Data are expressed as the mean ± s.d. of the experiments performed in triplicate. *P < 0.05, **P < 0.01.
Figure 2

TUG1 promotes tumor proliferation in U2OS cells. (A) U2OS cells were transfected with control siRNA or lncRNA TUG1 siRNA. In 48h, the cells were harvested for examining knockdown effect. (B) U2OS cells were transfected with control siRNA or lncRNA TUG1 siRNA. In 24h, cells were trypsinized and seeded into four 96-well plates at a density of 3×103 cells for MTT assay as described under Materials and Methods. Data are expressed as the mean ± s.d. of the experiments performed in triplicate. *P < 0.05, **P < 0.01.

3.2 TUG1 modulated the AKT signaling

To further understand the possible mechanisms that govern the pro-growth function of TUG1 in U2OS cells, we detected proliferation-related molecules including proliferating cell nuclear antigen (PCNA) and the well known AKT signaling pathway. As shown in Figure 3, after TUG1 was knocked down, the expression of PCNA was decreased, reflecting the growth inhibition at the molecule level. In addition, we found that the phosphor-AKT (at Ser 473) was also decreased in the TUG1-siRNA group, whereas the total AKT expression was unchanged. Since the phosphorylated AKT was an important transducer of AKT signaling pathway, this result suggested that the oncogenic activity of TUG1 might act through this pathway at least partially.

Figure 3 Knockdown of TUG1 reduces survival markers in vitro. U2OS cells were transfected with control siRNA or lncRNA TUG1 siRNA. Forty-eight hours later, cells were harvested for western blotting. Protein level of PCNA, p-Akt (S473) and t-Akt were tested. β-actin was used as the loading control in western blotting. The results showed that inhibited expression of TUG1 suppressed cell proliferation marker PCNA, and also suppressed cell survival marker p-Akt.
Figure 3

Knockdown of TUG1 reduces survival markers in vitro. U2OS cells were transfected with control siRNA or lncRNA TUG1 siRNA. Forty-eight hours later, cells were harvested for western blotting. Protein level of PCNA, p-Akt (S473) and t-Akt were tested. β-actin was used as the loading control in western blotting. The results showed that inhibited expression of TUG1 suppressed cell proliferation marker PCNA, and also suppressed cell survival marker p-Akt.

4 Discussion

Osteosarcoma is the most common primary bone malignant tumor in children and young adults. Although it has small incidence, the high degree of malignancy makes it a second leading cause of cancer-related death in this age group [18]. The 5-year survival rate is about 65% for patients with localized osteosarcoma, however, it decreases to only about 20% for these cases with metastasis [19-20].

Moreover, objective and reliable diagnostic biomarkers and effective targeted therapeutic agents are also lacking. Thus, further elucidating the underlying mechanisms of osteosarcoma is urgently required. According to the recent studies, lncRNAs emerge as a new frontier of translational research from molecular biology to cancer in the clinic.

TUG1 has been reported in osteosarcoma to be abnormally expressed and accelerates cell proliferation. However, the precise mechanisms or the specific signaling pathways it involves remain unknown. In the present study, we similarly demonstrated its upregulation in four osteosarcoma cell lines, compared to the normal control cells. In in vitro experiments, we found that after TUG1 was inhibited, the growth rate of U2OS cells was reduced. These findings once again confirmed the former study [17]. Besides, we found that TUG1 might regulate the expression of PCNA, and phosho-AKT (at Ser 473), but the total level of AKT remains unchanged after TUG1 was knocked down. The AKT pathway or PI3K-AKT pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. AKT is activated by phosphorylation at several sites. Activated AKT mediates downstream responses, including cell survival, growth, proliferation, cell migration and angiogenesis, by phosphorylating a range of intracellular proteins. Our results indicated that TUG1 might promote cell proliferation in osteosarcoma cells through AKT signaling pathway.

In summary, we demonstrated that TUG1 was increased and promoted cell proliferation in osteosarcoma cells. Mechanically, we proved that AKT signaling was involved in this oncogenic regulation. Further studies need to be carried out to verify its pro-tumor activity and clarify the mechanisms in detail.

Conflict of interest statement

Authors state no conflict of interest.

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Received: 2016-3-8
Accepted: 2016-4-5
Published Online: 2016-5-30
Published in Print: 2016-1-1

© 2016 Feng Yun-Bo et al.

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

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https://doi.org/10.1515/med-2016-0031
Keywords for this article
TUG1; osteosarcoma; proliferation; AKT
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  16. Association of HOTAIR expression with PI3K/Akt pathway activation in adenocarcinoma of esophagogastric junction
  17. Research Article
  18. The role of interleukin genes in the course of depression
  19. Case Report
  20. A rare case of primary pulmonary diffuse large B cell lymphoma with CD5 positive expression
  21. Research Article
  22. DWI and SPARCC scoring assess curative effect of early ankylosing spondylitis
  23. Research Article
  24. The diagnostic value of serum CEA, NSE and MMP-9 for on-small cell lung cancer
  25. Case Report
  26. Dysphonia – the single symptom of rifampicin resistant laryngeal tuberculosis
  27. Review Article
  28. Development of epidermal growth factor receptor tyrosine kinase inhibitors against EGFR T790M. Mutation in non small-cell lung carcinoma
  29. Research Article
  30. Negative regulation of CDC42 expression and cell cycle progression by miR-29a in breast cancer
  31. Research Article
  32. Expression analysis of the TGF-β/SMAD target genes in adenocarcinoma of esophagogastric junction
  33. Research Article
  34. Blood cells in thyroid cancer patients: a possible influence of apoptosis
  35. Research Article
  36. Detected EGFR mutation in cerebrospinal fluid of lung adenocarcinoma patients with meningeal metastasis
  37. Mini-review
  38. Pathogenesis-oriented approaches for the management of corticosteroid-resistant or relapsedprimary immune thrombocytopenia
  39. Research Article
  40. GSTP1 A>G polymorphism and chemosensitivity of osteosarcoma: A meta-analysis
  41. Research Article
  42. A meta-analysis of adiponectin gene rs22411766 T>G polymorphism and ischemic stroke susceptibility
  43. Research Article
  44. The diagnosis and pathological value of combined detection of HE4 and CA125 for patients with ovarian cancer
  45. Research Article
  46. SOX7 inhibits tumor progression of glioblastoma and is regulated by miRNA-24
  47. Research Article
  48. Sevoflurane affects evoked electromyography monitoring in cerebral palsy
  49. Case Report
  50. A case report of hereditary spherocytosis with concomitant chronic myelocytic leukemia
  51. Case Report
  52. A case of giant saphenous vein graft aneurysm followed serially after coronary artery bypass surgery
  53. Research Article
  54. LncRNA TUG1 is upregulated and promotes cell proliferation in osteosarcoma
  55. Review Article
  56. Meningioma recurrence
  57. Case Report
  58. Endobronchial amyloidosis mimicking bronchial asthma: a case report and review of the literature
  59. Case Report
  60. A confusing case report of pulmonary langerhans cell histiocytosis and literature review
  61. Research Article
  62. Effect of hesperetin on chaperone activity in selenite-induced cataract
  63. Research Article
  64. Clinical value of self-assessment risk of osteoporosis in Chinese
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  66. Correlation analysis of VHL and Jade-1 gene expression in human renal cell carcinoma
  67. Research Article
  68. Is acute appendicitis still misdiagnosed?
  69. Retraction
  70. Retraction of: application of food-specific IgG antibody detection in allergy dermatosis
  71. Review Article
  72. Platelet Rich Plasma: a short overview of certain bioactive components
  73. Research Article
  74. Correlation between CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility. A meta-analysis
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  76. Standards of anesthesiology practice during neuroradiological interventions
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  78. Expression and clinical significance of LXRα and SREBP-1c in placentas of preeclampsia
  79. Letter to the Editor
  80. ARDS diagnosed by SpO2/FiO2 ratio compared with PaO2/FiO2 ratio: the role as a diagnostic tool for early enrolment into clinical trials
  81. Research Article
  82. Impact of sensory integration training on balance among stroke patients: sensory integration training on balance among stroke patients
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  84. MicroRNAs as regulatory elements in psoriasis
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  86. Influenza A(H1N1)pdm09 and postpandemic influenza in Lithuania
  87. Review Article
  88. Garengeot’s hernia: two case reports with CT diagnosis and literature review
  89. Research Article
  90. Concept of experimental preparation for treating dentin hypersensitivity
  91. Research Article
  92. Hydrogen water reduces NSE, IL-6, and TNF-α levels in hypoxic-ischemic encephalopathy
  93. Research Article
  94. Xanthogranuloma of the sellar region diagnosed by frozen section
  95. Case Report
  96. Laparoscopic antegrade cholecystectomy: a standard procedure?
  97. Case Report
  98. Maxillary fibrous dysplasia associated with McCune-Albright syndrome. A case study
  99. Regular Article
  100. Sialoendoscopy, sialography, and ultrasound: a comparison of diagnostic methods
  101. Research Article
  102. Antibody Response to Live Attenuated Vaccines in Adults in Japan
  103. Conference article
  104. Excellence and safety in surgery require excellent and safe tutoring
  105. Conference article
  106. Suggestions on how to make suboptimal kidney transplantation an ethically viable option
  107. Regular Article
  108. Ectopic pregnancy treatment by combination therapy
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  110. Use of a simplified consent form to facilitate patient understanding of informed consent for laparoscopic cholecystectomy
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  112. Cusum analysis for learning curve of videothoracoscopic lobectomy
  113. Regular Article
  114. A meta-analysis of association between glutathione S-transferase M1 gene polymorphism and Parkinson’s disease susceptibility
  115. Conference article
  116. Plastination: ethical and medico-legal considerations
  117. Regular Article
  118. Investigation and control of a suspected nosocomial outbreak of pan-drug resistant Acinetobacter baumannii in an intensive care unit
  119. Regular Article
  120. Multifactorial analysis of fatigue scale among nurses in Poland
  121. Regular Article
  122. Smoking cessation for free: outcomes of a study of three Romanian clinics
  123. Regular Article
  124. Clinical efficacy and safety of tripterygium glycosides in treatment of stage IV diabetic nephropathy: A meta-analysis
  125. Special Issue on Italian Society for the Study of Vascular Anomalies
  126. Prevention and treatment of peritoneal adhesions in patients affected by vascular diseases following surgery: a review of the literature
  127. Special Issue on Italian Society for the Study of Vascular Anomalies
  128. Surgical treatment of recidivist lymphedema
  129. Special Issue on Italian Society for the Study of Vascular Anomalies
  130. CT and MR imaging of the thoracic aorta
  131. Special Issue on Italian Society for the Study of Vascular Anomalies
  132. Role of FDG-PET scan in staging of pulmonary epithelioid hemangioendothelioma
  133. Special Issue on Italian Society for the Study of Vascular Anomalies
  134. Sternal reconstruction by extracellular matrix: a rare case of phaces syndrome
  135. Special Issue on Italian Society for the Study of Vascular Anomalies
  136. Prenatal diagnosis, 3-D virtual rendering and lung sparing surgery by ligasure device in a baby with “CCAM and intralobar pulmonary sequestration”
  137. Special Issue on Italian Society for the Study of Vascular Anomalies
  138. Serum levels of inhibin B in adolescents after varicocelelectomy: A long term follow up
  139. Special Issue on Italian Society for the Study of Vascular Anomalies
  140. Our experience in the treatment of Malignant Fibrous Hystiocytoma of the larynx: clinical diagnosis, therapeutic approach and review of literature
  141. Special Issue on Italian Society for the Study of Vascular Anomalies
  142. Delayed recurrent nerve paralysis following post-traumatic aortic pseudoaneurysm
  143. Special Issue on Italian Society for the Study of Vascular Anomalies
  144. Integrated therapeutic approach to giant solitary fibrous tumor of the pleura: report of a case and review of the literature
  145. Special Issue on Italian Society for the Study of Vascular Anomalies
  146. Celiac axis compression syndrome: laparoscopic approach in a strange case of chronic abdominal pain in 71 years old man
  147. Special Issue on Italian Society for the Study of Vascular Anomalies
  148. A rare case of persistent hypoglossal artery associated with contralateral proximal subclavian stenosis
  149. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  150. Contralateral risk reducing mastectomy in Non-BRCA-Mutated patients
  151. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  152. Professional dental and oral surgery liability in Italy: a comparative analysis of the insurance products offered to health workers
  153. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  154. Informed consent in robotic surgery: quality of information and patient perception
  155. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  156. Malfunctions of robotic system in surgery: role and responsibility of surgeon in legal point of view
  157. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  158. Medicolegal implications of surgical errors and complications in neck surgery: A review based on the Italian current legislation
  159. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  160. Iatrogenic splenic injury: review of the literature and medico-legal issues
  161. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  162. Donation of the body for scientific purposes in Italy: ethical and medico-legal considerations
  163. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  164. Cosmetic surgery: medicolegal considerations
  165. Focus on Medico-Legal and Ethical Topics in Surgery in Italy
  166. Voluntary termination of pregnancy (medical or surgical abortion): forensic medicine issues
  167. Review Article
  168. Role of Laparoscopic Splenectomy in Elderly Immune Thrombocytopenia
  169. Review Article
  170. Endoscopic diagnosis and treatment of neuroendocrine tumors of the digestive system
  171. Review Article
  172. Efficacy and safety of splenectomy in adult autoimmune hemolytic anemia
  173. Research Article
  174. Relationship between gastroesophageal reflux disease and Ph nose and salivary: proposal of a simple method outpatient in patients adults
  175. Case Report
  176. Idiopathic pleural panniculitis with recurrent pleural effusion not associated with Weber-Christian disease
  177. Research Article
  178. Morbid Obesity: treatment with Bioenterics Intragastric Balloon (BIB), psychological and nursing care: our experience
  179. Research Article
  180. Learning curve for endorectal ultrasound in young and elderly: lights and shades
  181. Case Report
  182. Uncommon primary hydatid cyst occupying the adrenal gland space, treated with laparoscopic surgical approach in an old patient
  183. Research Article
  184. Distraction techniques for face and smile aesthetic preventing ageing decay
  185. Research Article
  186. Preoperative high-intensity training in frail old patients undergoing pulmonary resection for NSCLC
  187. Review Article
  188. Descending necrotizing mediastinitis in the elderly patients
  189. Research Article
  190. Prophylactic GSV surgery in elderly candidates for hip or knee arthroplasty
  191. Research Article
  192. Diagnostic yield and safety of C-TBNA in elderly patients with lung cancer
  193. Research Article
  194. The learning curve of laparoscopic holecystectomy in general surgery resident training: old age of the patient may be a risk factor?
  195. Research Article
  196. Self-gripping mesh versus fibrin glue fixation in laparoscopic inguinal hernia repair: a randomized prospective clinical trial in young and elderly patients
  197. Research Article
  198. Anal sphincter dysfunction in multiple sclerosis: an observation manometric study
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