Long non-coding RNAs (lncRNAs) can modulate gene expression through different mechanisms, but the fundamental molecular mechanism between lncRNAs and MET protein in diffuse large B-cell lymphoma (DLBCL) was poorly understood. The expression of lncRNA TUG1 and MET in DLBCL tissues and cell lines was determined by quantitative real-time PCR and western blotting. Cell proliferation, invasion and apoptosis were determined by cell counting kit-8 assay, transwell assay and flow cytometer. The animal xenograft model was established by the injection of DLBCL cells carrying si-TUG1. The expression of TUG1 and MET was upregulated in DLBCL tissues and cells. We demonstrated that MET was altered in the TUG1 knockdown DLBCL cells, and confirmed the interaction between TUG1 and MET by RNA pull-down and RNA immunoprecipitation. Furthermore, knockdown of TUG1 reduced MET protein level by promoting ubiquitination, and suppressed tumor growth in vitro and in vivo. Our findings demonstrated that TUG1 exerted its oncogenic function in DLBCL by inhibiting the ubiquitination and the subsequent degradation of MET. Knockdown of TUG1 through MET downregulation suppressed DLBCL cell proliferation and tumor growth.
Diffuse large B-cell lymphoma Invasion Long non-coding RNA MET TUG1 Ubiquitination
This is a preview of subscription content, log in to check access.
This study was supported by the National Natural Science Foundation of China (Grant Nos. 81871263, 81770223, 81500097, and 81500088).
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflict of interest.
This study was approved by the Institute Research Medical Ethics Committee of The Affiliated Hospital of Xuzhou Medical University.
All the patients were participating in this study with written informed consent.
Research involving human and animal participants
All animal experiments were proved by the Institute Research Medical Ethics Committee of Xuzhou Medical University, and all animals-treatment operations were executed according to the Xuzhou Medical University Ethical Guidelines for Animal Experiment.
Green TM, Young KH, Visco C et al (2012) Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30(28):3460–3467PubMedCrossRefGoogle Scholar
Xu-Monette ZY, Wu L, Visco C et al (2013) Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with Rituximab-CHOP: a report from an international DLBCL Rituximab-CHOP consortium program study. Clin Lymphoma Myeloma Leukemia 13:S382CrossRefGoogle Scholar
Castillo JJ, Winer ES, Olszewski AJ (2014) Sites of extranodal involvement are prognostic in patients with diffuse large B-cell lymphoma in the rituximab era: an analysis of the Surveillance, Epidemiology and End Results database. Am J Hematol 89(3):310–314PubMedCrossRefGoogle Scholar
Saito B, Shiozawa E, Usui T et al (2007) Rituximab with chemotherapy improves survival of non-germinal center type untreated diffuse large B-cell lymphoma. Leukemia 21(12):2563–2566PubMedCrossRefGoogle Scholar
Sehn LH, Gascoyne RD (2015) Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood 125(1):22PubMedCrossRefGoogle Scholar
Bottaro DP, Rubin JS, Faletto DL et al (1991) Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251(4995):802CrossRefGoogle Scholar
Livio T, Paolo MC (2002) Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2(4):289–300CrossRefGoogle Scholar
Renzo MF, Di Olivero M, Ferro S et al (1992) Overexpression of the c-MET/HGF receptor gene in human thyroid carcinomas. Oncogene 7(12):2549–2553PubMedGoogle Scholar
Humphrey PA, Zhu X, Zarnegar R et al (1995) Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol 147(2):386PubMedPubMedCentralGoogle Scholar
Yonemura Y, Kaji M, Hirono Y et al (1996) Correlation between overexpression of c-met gene and the progression of gastric cancer. Int J Oncol 8(3):555PubMedGoogle Scholar
Mahtouk K, Tjin EPM, Spaargaren M, Pals ST (2010) The HGF/MET pathway as target for the treatment of multiple myeloma and B-cell lymphomas. BBA—Rev Cancer 1806(2):208–219Google Scholar
Kawano R, Ohshima K, Karube K et al (2004) Prognostic significance of hepatocyte growth factor and c-MET expression in patients with diffuse large B-cell lymphoma. Br J Haematol 127(3):305PubMedCrossRefGoogle Scholar
Kang Won J, Jeong Eun L, Sun Young K et al (2011) The C-terminus of Hsp70-interacting protein promotes Met receptor degradation. J Thoracic Oncol 6(4):679–687CrossRefGoogle Scholar
Caley DP, Pink RC, Trujillano D, Carter DR (2010) Long noncoding RNAs, chromatin, and development. Sci World J 10(1):90CrossRefGoogle Scholar
Zhou YX, Mao LW, Wang YL (2017) Increased LncRNA PVT-1 is associated with tumor proliferation and predicts poor prognosis in cervical cancer. Clin Surg Res Commun 1(1):10–17CrossRefGoogle Scholar
Wang Y, Zhang M, Xu H et al (2017) Discovery and validation of the tumor-suppressive function of long noncoding RNA PANDA in human diffuse large B-cell lymphoma through the inactivation of MAPK/ERK signaling pathway. Oncotarget 8(42):72182–72196PubMedPubMedCentralGoogle Scholar
Deng L, Jiang L, Tseng K-F et al (2018) Aberrant NEAT1_1 expression may be a predictive marker of poor prognosis in diffuse large B cell lymphoma. Cancer Biomark 23(2):157–164PubMedCrossRefGoogle Scholar
Dousti F, Shahrisa A, Ansari H et al (2018) Long non-coding RNAs expression levels in diffuse large B-cell lymphoma: an in silico analysis. Pathology—Res Pract 214(9):1462–1466CrossRefGoogle Scholar
Eis PS, Tam W, Sun L et al (2005) Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci USA 102(10):3627–3632PubMedCrossRefGoogle Scholar
Wang Z-Q, He C-Y, Hu L et al (2017) Long noncoding RNA UCA1 promotes tumour metastasis by inducing GRK2 degradation in gastric cancer. Cancer Lett 408:10–21PubMedCrossRefGoogle Scholar
Wang K, Long B, Zhou L-Y et al (2014) CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation. Nat Commun 5:3596PubMedCrossRefGoogle Scholar
Kang WJ, Lee JE, Sun YK et al (2011) The C-terminus of Hsp70-Interacting Protein Promotes Met Receptor Degradation. J Thoracic Oncol 6(4):679–687CrossRefGoogle Scholar
Zhang J, Grubor V, Love CL et al (2013) Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci USA 110(4):1398–1403PubMedCrossRefGoogle Scholar
Youtao X, Jie W, Mantang Q et al (2015) Upregulation of the long noncoding RNA TUG1 promotes proliferation and migration of esophageal squamous cell carcinoma. Tumor Biol 36(3):1643–1651CrossRefGoogle Scholar
Jiemei T, Kaifeng Q, Mingyi L, Ying L (2016) Double-negative feedback loop between long non-coding RNA TUG1 and miR-145 promotes epithelial to mesenchymal transition and radioresistance in human bladder cancer cells. FEBS Lett 589:3175–3181Google Scholar
Heng C, Yixue X, Ping W et al (2015) The long noncoding RNA TUG1 regulates blood-tumor barrier permeability by targeting miR-144. Oncotarget 6(23):19759–19779Google Scholar
Lin YH, Wu MH, Huang YH et al (2017) Taurine upregulated gene 1 functions as a master regulator to coordinate glycolysis and metastasis in hepatocellular carcinoma. Hepatology 67(1):188–203PubMedCrossRefGoogle Scholar
Ma B, Li M, Zhang L et al (2015) Upregulation of long non-coding RNA TUG1 correlates with poor prognosis and disease status in osteosarcoma. Tumor Biol 37(4):1–11Google Scholar
Sun J, Ding C, Yang Z et al (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(1):42PubMedPubMedCentralCrossRefGoogle Scholar
Tjin EPM, Groen RWJ, Vogelzang I et al (2006) Functional analysis of HGF/MET signaling and aberrant HGF-activator expression in diffuse large B-cell lymphoma. Blood 107(2):760PubMedCrossRefGoogle Scholar
Shahab U, Hussain AR, Maqbool A et al (2010) Inhibition of c-MET is a potential therapeutic strategy for treatment of diffuse large B-cell lymphoma. Lab Invest 90(9):1346–1356CrossRefGoogle Scholar
Uddin S, Hussain AR, Ahmed M et al (2010) Inhibition of fatty acid synthase suppresses c-Met receptor kinase and induces apoptosis in diffuse large B-cell lymphoma. Mol Cancer Ther 9(5):1244–1255PubMedCrossRefGoogle Scholar
Jia YJ, Liu ZB, Wang WG et al (2017) HDAC6 regulates microRNA-27b that suppresses proliferation, promotes apoptosis and target MET in diffuse large B-cell lymphoma. Leukemia. 32(3):703PubMedCrossRefGoogle Scholar