Long non-coding RNA taurine-upregulated gene 1 correlates with poor prognosis, induces cell proliferation, and represses cell apoptosis via targeting aurora kinase A in adult acute myeloid leukemia
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This study aimed to investigate the correlation of long non-coding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) with clinicopathological feature and prognosis, and to explore its effect on cell proliferation and apoptosis as well as the relevant target genes in adult acute myeloid leukemia (AML). LncRNA TUG1 expression was detected in bone marrow samples from 186 AML patients and 62 controls. Blank mimic, lncRNA TUG1 mimic, blank inhibitor, and lncRNA TUG1 inhibitor lentivirus vectors were transfected in KG-1 cells. Rescue experiment was performed by transfection of lncRNA TUG1 inhibitor and aurora kinase A (AURKA) mimic lentivirus vectors. Cell proliferation, apoptosis, RNA, and protein expressions were determined by CKK-8, annexin V-FITC-propidium iodide, quantitative polymerase chain reaction, and western blot assays. LncRNA TUG1 expression was higher in AML patients compared to controls and correlated with higher white blood cell counts, monosomal karyotype, FLT3-ITD mutation, poor-risk stratification, and poor prognosis, which independently predicted worse event-free survival and overall survival. In vitro, lncRNA TUG1 expression was higher in AML cell lines (KG-1, MOLM-14, HL-60, NB-4, and THP-1 cells) compared to controls. LncRNA TUG1 mimic promoted cell proliferation and decreased cell apoptosis rate, while lncRNA TUG1 inhibitor repressed cell proliferation and increased cell apoptosis rate. Rescue experiment showed that AURKA attenuated the influence of lncRNA TUG1 on AML cell proliferation and apoptosis. In conclusion, lncRNA TUG1 associates with advanced disease and worse prognosis in adult AML patients, and it induces AML cell proliferation and represses cell apoptosis via targeting AURKA.
KeywordsLncRNA TUG1 Acute myeloid leukemia (AML) AURKA Cell proliferation Cell apoptosis
This study was supported by the National Natural Science Foundation of China (No. 81201857) and Nantong Science and Technology Project Foundation, China (No. MS12016012).
Compliance with ethical standards
This study was performed under the Institutional Review Board approvals from The Affiliated Hospital of Nantong University Hospital and conducted in accordance with the Declaration of Helsinki. Written informed consents had been obtained from all patients and controls.
Conflict of interest
The authors declare that they have no conflict of interest.
- 4.Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Roder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K, Bell I, Chakrabortty S, Chen X, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Falconnet E, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Gunawardena H, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Luo OJ, Park E, Persaud K, Preall JB, Ribeca P, Risk B, Robyr D, Sammeth M, Schaffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Ruan X, Hayashizaki Y, Harrow J, Gerstein M, Hubbard T, Reymond A, Antonarakis SE, Hannon G, Giddings MC, Ruan Y, Wold B, Carninci P, Guigo R, Gingeras TR (2012) Landscape of transcription in human cells. Nature 489(7414):101–108. https://doi.org/10.1038/nature11233 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Pinero J, Bravo A, Queralt-Rosinach N, Gutierrez-Sacristan A, Deu-Pons J, Centeno E, Garcia-Garcia J, Sanz F, Furlong LI (2017) DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res 45(D1):D833–D839. https://doi.org/10.1093/nar/gkw943 CrossRefPubMedGoogle Scholar
- 16.Pan JQ, Zhang YQ, Wang JH, Xu P, Wang W (2017) lncRNA co-expression network model for the prognostic analysis of acute myeloid leukemia. Int J Mol Med. https://doi.org/10.3892/ijmm.2017.2888
- 19.Iliev R, Kleinova R, Juracek J, Dolezel J, Ozanova Z, Fedorko M, Pacik D, Svoboda M, Stanik M, Slaby O (2016) Overexpression of long non-coding RNA TUG1 predicts poor prognosis and promotes cancer cell proliferation and migration in high-grade muscle-invasive bladder cancer. Tumour Biol 37(10):13385–13390. https://doi.org/10.1007/s13277-016-5177-9 CrossRefPubMedGoogle Scholar
- 20.Zhang E, He X, Yin D, Han L, Qiu M, Xu T, Xia R, Xu L, Yin R, De W (2016) Increased expression of long noncoding RNA TUG1 predicts a poor prognosis of gastric cancer and regulates cell proliferation by epigenetically silencing of p57. Cell Death Dis 7:e2109. https://doi.org/10.1038/cddis.2015.356 CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Sun J, Ding C, Yang Z, Liu T, Zhang X, Zhao C, Wang J (2016) The long non-coding RNA TUG1 indicates a poor prognosis for colorectal cancer and promotes metastasis by affecting epithelial-mesenchymal transition. J Transl Med 14:42. https://doi.org/10.1186/s12967-016-0786-z CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Zeng B, Ye H, Chen J, Cheng D, Cai C, Chen G, Chen X, Xin H, Tang C, Zeng J (2017) LncRNA TUG1 sponges miR-145 to promote cancer progression and regulate glutamine metabolism via Sirt3/GDH axis. Oncotarget 8(69):113650–113661. https://doi.org/10.18632/oncotarget.21922 PubMedPubMedCentralCrossRefGoogle Scholar
- 23.Guo P, Zhang G, Meng J, He Q, Li Z, Guan Y (2018) Upregulation of long non-coding RNA TUG1 promotes bladder cancer cell 5 proliferation, migration and invasion by inhibiting miR-29c. Oncol Res. https://doi.org/10.3727/096504018X15152085755247
- 24.Fang T, Huang H, Li X, Liao J, Yang Z, Hoffman RM, Cheng XI, Liang L, Hu W, Yun S (2018) Effects of siRNA silencing of TUG1 and LCAL6 long non-coding RNAs on patient-derived xenograft of non-small cell lung cancer. Anticancer Res 38(1):179–186. https://doi.org/10.21873/anticanres.12206 PubMedCrossRefGoogle Scholar
- 25.Jiang L, Wang W, Li G, Sun C, Ren Z, Sheng H, Gao H, Wang C, Yu H (2016) High TUG1 expression is associated with chemotherapy resistance and poor prognosis in esophageal squamous cell carcinoma. Cancer Chemother Pharmacol 78(2):333–339. https://doi.org/10.1007/s00280-016-3066-y CrossRefPubMedGoogle Scholar
- 31.Chuang TP, Wang JY, Jao SW, Wu CC, Chen JH, Hsiao KH, Lin CY, Chen SH, Su SY, Chen YJ, Chen YT, Wu DC, Li LH (2016) Over-expression of AURKA, SKA3 and DSN1 contributes to colorectal adenoma to carcinoma progression. Oncotarget 7(29):45803–45818. https://doi.org/10.18632/oncotarget.9960 CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Eterno V, Zambelli A, Villani L, Tuscano A, Manera S, Spitaleri A, Pavesi L, Amato A (2016) AurkA controls self-renewal of breast cancer-initiating cells promoting wnt3a stabilization through suppression of miR-128. Sci Rep 6:28436. https://doi.org/10.1038/srep28436 CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Wu J, Yang L, Shan Y, Cai C, Wang S, Zhang H (2016) AURKA promotes cell migration and invasion of head and neck squamous cell carcinoma through regulation of the AURKA/Akt/FAK signaling pathway. Oncol Lett 11(3):1889–1894. https://doi.org/10.3892/ol.2016.4110 CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Lucena-Araujo AR, de Oliveira FM, Leite-Cueva SD, dos Santos GA, Falcao RP, Rego EM (2011) High expression of AURKA and AURKB is associated with unfavorable cytogenetic abnormalities and high white blood cell count in patients with acute myeloid leukemia. Leuk Res 35(2):260–264. https://doi.org/10.1016/j.leukres.2010.07.034 CrossRefPubMedGoogle Scholar
- 35.Ye D, Garcia-Manero G, Kantarjian HM, Xiao L, Vadhan-Raj S, Fernandez MH, Nguyen MH, Medeiros LJ, Bueso-Ramos CE (2009) Analysis of Aurora kinase A expression in CD34(+) blast cells isolated from patients with myelodysplastic syndromes and acute myeloid leukemia. J Hematop 2(1):2–8. https://doi.org/10.1007/s12308-008-0019-3 CrossRefPubMedGoogle Scholar
- 36.Huang XF, Luo SK, Xu J, Li J, Xu DR, Wang LH, Yan M, Wang XR, Wan XB, Zheng FM, Zeng YX, Liu Q (2008) Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia. Blood 111(5):2854–2865. https://doi.org/10.1182/blood-2007-07-099325 CrossRefPubMedGoogle Scholar