Abstract
Recent studies have shown that long non-coding RNAs (lncRNAs) have critical roles in tumorigenesis, including osteosarcoma. The lncRNA taurine-upregulated gene 1 (TUG1) was reported to be involved in the progression of osteosarcoma. Here, we investigated the role of TUG1 in osteosarcoma cells and the underlying mechanism. TUG1 expression was measured in osteosarcoma cell lines and human normal osteoblast cells by quantitative real-time PCR (qRT-PCR). The effects of TUG1 on osteosarcoma cells were studied by RNA interference in vitro and in vivo. The mechanism of competing endogenous RNA (ceRNA) was determined using bioinformatic analysis and luciferase assays. Our data showed that TUG1 knockdown inhibited cell proliferation and colony formation, and induced G0/G1 cell cycle arrest and apoptosis in vitro, and suppressed tumor growth in vivo. Besides, we found that TUG1 acted as an endogenous sponge to directly bind to miR-9-5p and downregulated miR-9-5p expression. Moreover, TUG1 overturned the effect of miR-9-5p on the proliferation, colony formation, cell cycle arrest, and apoptosis in osteosarcoma cells, which involved the derepression of POU class 2 homeobox 1 (POU2F1) expression. In conclusion, our study elucidated a novel TUG1/miR-9-5p/POU2F1 pathway, in which TUG1 acted as a ceRNA by sponging miR-9-5p, leading to downregulation of POU2F1 and facilitating the tumorigenesis of osteosarcoma. These findings may contribute to the lncRNA-targeted therapy for human osteosarcoma.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004. Cancer. 2009;115:1531–43.
Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival-a report from the Children’s Oncology Group. J Clin Oncol. 2008;26:633–8.
Kobayashi E, Hornicek FJ, Duan Z. MicroRNA involvement in osteosarcoma. Sarcoma. 2012;2012.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.
Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43:904–14.
Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.
Kallen AN, Zhou XB, Xu J, Qiao C, Ma J, Yan L, et al. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol Cell. 2013;52:101–12.
Wang K, Long B, Zhou LY, Liu F, Zhou QY, Liu CY, et al. CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation. Nat Commun. 2014;5:3596.
Young T, Matsuda T, Cepko C. The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina. Curr Biol. 2005;15:501–12.
Xu Y, Wang J, Qiu M, Xu L, Li M, Jiang F, et al. Upregulation of the long noncoding RNA TUG1 promotes proliferation and migration of esophageal squamous cell carcinoma. Tumor Biol. 2015;36:1643–51.
Zhang E, Yin D, Sun M, Kong R, Liu X, You L, et al. P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression. Cell Death Dis. 2014;5:e1243.
Ji TT, Huang X, Jin J, Pan SH, Zhuge XJ. Inhibition of long non-coding RNA TUG1 on gastric cancer cell transference and invasion through regulating and controlling the expression of miR-144/c-met axis. Asian Pac J of Trop Med. 2016;9:508–12.
Zhang Q, Geng PL, Yin P, Wang XL, Jia JP, Yao J. Down-regulation of long non-coding RNA TUG1 inhibits osteosarcoma cell proliferation and promotes apoptosis. Asian Pac J Cancer Prev. 2013;14:2311–5.
Ma B, Li M, Zhang L, Huang M, Lei JB, Fu GH, et al. Upregulation of long non-coding RNA TUG1 correlates with poor prognosis and disease status in osteosarcoma. Tumor Biol. 2015;1-11.
Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 2009;458:223–7.
Yuan SX, Yang F, Yang Y, Tao QF, Zhang J, Huang G, et al. Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients’ poor recurrence-free survival after hepatectomy. Hepatology. 2012;56:2231–41.
Dhamija S, Diederichs S. From junk to master regulators of invasion: lncRNA functions in migration, EMT and metastasis. Int J Cancer. 2016;139:269–80.
Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell. 2011;147:358–69.
Zhou M, Wang X, Shi H, Cheng L, Wang Z, Zhao H, et al. Characterization of long non-coding RNA-associated ceRNA network to reveal potential prognostic lncRNA biomarkers in human ovarian cancer. Oncotarget. 2016;7:12598–611.
Xie J, Guo B, Ding Z, Kang J, Deng X, Wu B, et al. Microarray analysis of lncRNAs and mRNAs co-expression network and lncRNA function as ceRNA in papillary thyroid carcinoma. J Biomater Tissue Eng. 2015;5:872–80.
Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014;505:344–52.
Wang F, Ying HQ, He BS, Pan YQ, Deng QW, Sun HL, et al. Upregulated lncRNA-UCA1 contributes to progression of hepatocellular carcinoma through inhibition of miR-216b and activation of FGFR1/ERK signaling pathway. Oncotarget. 2015;6:7899–917.
Liu XH, Sun M, Nie FQ, Ge YB, Zhang EB, Yin DD, et al. Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol Cancer. 2014;13:92.
Ng M, Lam V, Tam C, Chan A, So WY, Ma R, et al. Association of the POU class 2 homeobox 1 gene (POU2F1) with susceptibility to type 2 diabetes in Chinese populations. Diabet Med. 2010;27:1443–9.
Sive HL, Roeder RG. Interaction of a common factor with conserved promoter and enhancer sequences in histone H2B, immunoglobulin, and U2 small nuclear RNA (snRNA) genes. Proc Natl Acad Sci U S A. 1986;83:6382–6.
Tantin D, Schild-Poulter C, Wang V, Haché RJ, Sharp PA. The octamer binding transcription factor Oct-1 is a stress sensor. Cancer Res. 2005;65:10750–8.
Sadikovic B, Yoshimoto M, Chilton-MacNeill S, Thorner P, Squire JA, Zielenska M. Identification of interactive networks of gene expression associated with osteosarcoma oncogenesis by integrated molecular profiling. Hum Mol Genet. 2009;18:1962–75.
Acknowledgments
This study was supported by the National Natural Science Foundation of China (Grant No: 81574002).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
All procedures for animal care were approved by the Animal Management Committee of Guangzhou Medical University.
Conflicts of interest
None
Rights and permissions
About this article
Cite this article
Xie, CH., Cao, YM., Huang, Y. et al. Long non-coding RNA TUG1 contributes to tumorigenesis of human osteosarcoma by sponging miR-9-5p and regulating POU2F1 expression. Tumor Biol. 37, 15031–15041 (2016). https://doi.org/10.1007/s13277-016-5391-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-016-5391-5