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Long non-coding RNA LINC02446 suppresses the proliferation and metastasis of bladder cancer cells by binding with EIF3G and regulating the mTOR signalling pathway

Cancer Gene Therapy volume 28, pages 1376–1389 (2021)Cite this article

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Abstract

Accumulating evidence has been obtained to understand the mechanisms of long non-coding RNAs (lncRNAs) in bladder cancer (BC). However, due to the recurrence and metastasis of BC, searching for lncRNAs that are related to prognosis and metastasis and exploring the pathogenesis of BC might provide new insights for the treatment of BC. In the present study, we used the TCGA and GEO databases and identified LINC02446 as associated with prognosis and differentially expressed in bladder cancer tissues and para-cancer tissues. Then, we found that LINC02446 could affect the proliferation, migration and invasion of BC cells. Additionally, we found that LINC02446 could bind to the EIF3G protein and regulate the protein stability of EIF3G and then inhibit the mTOR signalling pathway. In summary, all these findings show that LINC02446 might serve as a promising therapeutic target for BC intervention.

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Fig. 1: Identification of prognostic lncRNAs, establishment of the 38-lncRNA signature risk score and prediction of overall survival with the 38-lncRNA signature.
Fig. 2: Prognostic value of the 38- lncRNA signature, identification of 38-lncRNA signature correlated biological pathways and co-expression network.
Fig. 3: Gene expression microarray analyses in the GEO database and hub lncRNA selection.
Fig. 4: LINC02446 expression is downregulated and acts as a tumour suppressor in BC.
Fig. 5: LINC02446 binds with EIF3G and regulates the protein stability of EIF3G in BC cells.
Fig. 6: LINC02446 affects cell function and inhibits the mTOR signalling pathway in an EIF3G-mediated manner in BC.

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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  Google Scholar 

  2. Chen WQ, Li H, Sun KX, Zheng RS, Zhang SW, Zeng HM, et al. [Report of Cancer Incidence and Mortality in China, 2014]. Zhonghua Zhong Liu Za Zhi. 2018;40:5–13.

    CAS  PubMed  Google Scholar 

  3. Babjuk M, Burger M, Compérat EM, Gontero P, Mostafid AH, Palou J, et al. European Association of Urology Guidelines on non-muscle-invasive bladder cancer (TaT1 and Carcinoma In Situ)−2019 update. Eur Urol. 2019;76:639–57.

    Article  CAS  Google Scholar 

  4. Ucpinar B, Erbin A, Ayranci A, Caglar U, Alis D, Basal S, et al. Prediction of recurrence in non-muscle invasive bladder cancer patients. Do patient characterisics matter?. J Buon. 2019;24:1659–65.

    PubMed  Google Scholar 

  5. St LG, Wahlestedt C, Kapranov P. The landscape of long noncoding RNA classification. Trends Genet. 2015;31:239–51.

    Article  Google Scholar 

  6. Schmitz SU, Grote P, Herrmann BG. Mechanisms of long noncoding RNA function in development and disease. Cell Mol Life Sci. 2016;73:2491–509.

    Article  CAS  Google Scholar 

  7. Chen LL. Linking long noncoding RNA localization and function. Trends Biochem Sci. 2016;41:761–72.

    Article  CAS  Google Scholar 

  8. Bhan A, Soleimani M, Mandal SS. Long noncoding RNA and cancer: a new paradigm. Cancer Res. 2017;77:3965–81.

    Article  CAS  Google Scholar 

  9. Salamon I, Saccani JG, Condorelli G. The long noncoding RNA landscape in cardiovascular disease: a brief update. Curr Opin Cardiol. 2018;33:282–9.

    Article  Google Scholar 

  10. Luo Q, Chen Y. Long noncoding RNAs and Alzheimer’s disease. Clin Interv Aging. 2016;11:867–72.

    Article  CAS  Google Scholar 

  11. Yang Z, Jiang S, Shang J, Jiang Y, Dai Y, Xu B, et al. LncRNA: Shedding light on mechanisms and opportunities in fibrosis and aging. Ageing Res Rev. 2019;52:17–31.

    Article  CAS  Google Scholar 

  12. Delás MJ, Sabin LR, Dolzhenko E, Knott SR, Munera ME, Jackson BT, et al. lncRNA requirements for mouse acute myeloid leukemia and normal differentiation. Elife. 2017;6:e25607.

    Article  Google Scholar 

  13. Peng WX, Koirala P, Mo YY. LncRNA-mediated regulation of cell signaling in cancer. Oncogene. 2017;36:5661–7.

    Article  CAS  Google Scholar 

  14. Wei GH, Wang X. lncRNA MEG3 inhibit proliferation and metastasis of gastric cancer via p53 signaling pathway. Eur Rev Med Pharm Sci. 2017;21:3850–6.

    Google Scholar 

  15. Dong J, Teng F, Guo W, Yang J, Ding G, Fu Z. lncRNA SNHG8 promotes the tumorigenesis and metastasis by sponging miR-149-5p and predicts tumor recurrence in hepatocellular carcinoma. Cell Physiol Biochem. 2018;51:2262–74.

    Article  CAS  Google Scholar 

  16. Wang LX, Wan C, Dong ZB, Wang BH, Liu HY, Li Y. Integrative analysis of long noncoding RNA (lncRNA), microRNA (miRNA) and mRNA expression and construction of a competing endogenous RNA (ceRNA) network in metastatic melanoma. Med Sci Monit. 2019;25:2896–907.

    Article  CAS  Google Scholar 

  17. Ferrè F, Colantoni A, Helmer-Citterich M. Revealing protein-lncRNA interaction. Brief Bioinform. 2016;17:106–16.

    Article  Google Scholar 

  18. Cheng S, Zhang Y, Chen S, Zhou Y. LncRNA Hotair Participates in microglia activation and inflammatory factor release by regulating the ubiquitination of MYD88 in traumatic brain injury. J Mol Neurosci. 2021;71:169–77.

    Article  CAS  Google Scholar 

  19. Rouprêt M, Colin P, Xylinas E, Compérat E, Dubosq F, Houédé N, et al. [CCAFU french national guidelines 2016–2018 on upper tract tumors]. Prog Urol. 2016;27(Suppl 1):S55–S66.

    Article  Google Scholar 

  20. Bahrami S, Kazemi B, Zali H, Black PC, Basiri A, Bandehpour M, et al. Discovering therapeutic protein targets for bladder cancer using proteomic data analysis. Curr Mol Pharmacol. 2020;13:150–72.

    Article  CAS  Google Scholar 

  21. Anastasiadou E, Jacob LS, Slack FJ. Non-coding RNA networks in cancer. Nat Rev Cancer. 2018;18:5–18.

    Article  CAS  Google Scholar 

  22. Hombach S, Kretz M. Non-coding RNAs: classification, biology and functioning. Adv Exp Med Biol. 2016;937:3–17.

    Article  CAS  Google Scholar 

  23. Jarroux J, Morillon A, Pinskaya M. History, discovery, and classification of lncRNAs. Adv Exp Med Biol. 2017;1008:1–46.

    Article  CAS  Google Scholar 

  24. Andersen RE, Lim DA. Forging our understanding of lncRNAs in the brain. Cell Tissue Res. 2018;371:55–71.

    Article  CAS  Google Scholar 

  25. Darbellay F, Necsulea A. Comparative transcriptomics analyses across species, organs, and developmental stages reveal functionally constrained lncRNAs. Mol Biol Evol. 2020;37:240–59.

    Article  CAS  Google Scholar 

  26. Kazimierczyk M, Kasprowicz MK, Kasprzyk ME, Wrzesinski J. Human long noncoding RNA interactome: detection, characterization and function. Int J Mol Sci. 2020;21:1207.

    Article  Google Scholar 

  27. Tomczak K, Czerwińska P, Wiznerowicz M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Pozn). 2015;19(1A):A68–A77.

    Google Scholar 

  28. Beznosková P, Wagner S, Jansen ME, von der Haar T, Valášek LS. Translation initiation factor eIF3 promotes programmed stop codon readthrough. Nucleic Acids Res. 2015;43:5099–111.

    Article  Google Scholar 

  29. Dong Z, Zhang JT. Initiation factor eIF3 and regulation of mRNA translation, cell growth, and cancer. Crit Rev Oncol Hematol. 2006;59:169–80.

    Article  Google Scholar 

  30. Holm A, Lin L, Faraco J, Mostafavi S, Battle A, Zhu X, et al. EIF3G is associated with narcolepsy across ethnicities. Eur J Hum Genet. 2015;23:1573–80.

    Article  CAS  Google Scholar 

  31. Gomes-Duarte A, Lacerda R, Menezes J, Romão L. eIF3: a factor for human health and disease. RNA Biol. 2018;15:26–34.

    Article  Google Scholar 

  32. Yin Y, Long J, Sun Y, Li H, Jiang E, Zeng C, et al. The function and clinical significance of eIF3 in cancer. Gene. 2018;673:130–3.

    Article  CAS  Google Scholar 

  33. Yang C, Zhang Y, Du W, Cheng H, Li C. Eukaryotic translation initiation factor 3 subunit G promotes human colorectal cancer. Am J Transl Res. 2019;11:612–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Zheng Q, Liu H, Ye J, Zhang H, Jia Z, Cao J. Nuclear distribution of eIF3g and its interacting nuclear proteins in breast cancer cells. Mol Med Rep. 2016;13:2973–80.

    Article  CAS  Google Scholar 

  35. Nupponen NN, Isola J, Visakorpi T. Mapping the amplification of EIF3S3 in breast and prostate cancer. Genes Chromosome Cancer. 2000;28:203–10.

    Article  CAS  Google Scholar 

  36. Yang C, Liu X, Li C, Li S, Du W, Yang D. Eukaryotic translation initiation factor 3 subunit G (EIF3G) resensitized HCT116/5-Fu to 5-fluorouracil (5-Fu) via inhibition of MRP and MDR1. Onco Target Ther. 2018;11:5315–24.

    Article  CAS  Google Scholar 

  37. Dalton HM, Curran SP. Hypodermal responses to protein synthesis inhibition induce systemic developmental arrest and AMPK-dependent survival in Caenorhabditis elegans. PLOS Genet. 2018;14:e1007520.

    Article  Google Scholar 

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Acknowledgements

This work was supported by National Natural Science Fund [Grant No. 81672525], the Project of Liaoning Distinguished Professor (Grant No. [2012]145), Liaoning Natural Science Fund [Grant No. 201602830], Shenyang Plan Project of Science and Technology (Grant No. F17-230-9-08) and Shenyang clinical medicine research centre (Grant No. [2017]76), China Medical University’s 2017 discipline promotion programme (Grant No. 2017XK08), China Medical University’s 2018 discipline promotion programme. Funding agency did not participate in the design of the study and collection, analysis and interpretation of data and in writing the manuscript.

Funding

This work was supported by National Natural Science Fund [Grant No. 81672525], the Project of Liaoning Distinguished Professor (Grant No. [2012]145), Liaoning Natural Science Fund [Grant No. 201602830], Shenyang Plan Project of Science and Technology (Grant No. F17-230-9-08) and Shenyang clinical medicine research centre (Grant No. [2017]76), China Medical University’s 2017 discipline promotion programme (Grant No. 2017XK08), China Medical University’s 2018 discipline promotion programme.

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  1. Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, China

    Xiaotong Zhang, Jiarun Zhang, Wei Zhao, Xiao Dong, Peng Xin, Xi Liu, Xuejie Li, Zhifei Jing, Zhe Zhang, Chuize Kong & Xiuyue Yu

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Zhang, X., Zhang, J., Zhao, W. et al. Long non-coding RNA LINC02446 suppresses the proliferation and metastasis of bladder cancer cells by binding with EIF3G and regulating the mTOR signalling pathway. Cancer Gene Ther 28, 1376–1389 (2021). https://doi.org/10.1038/s41417-020-00285-2

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