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Long noncoding RNA UCA1 promotes the proliferation of hypoxic human pulmonary artery smooth muscle cells

  • Molecular and genomic physiology
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Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Our study explored the effects of lncRNA UCA1 on the proliferation and apoptosis in hypoxic human pulmonary artery smooth muscle cells (HPASMCs) and highlighted the endogenous relationship between UCA1, ING5, and hnRNP I in cell proliferation. Hypoxia-induced HPASMCs were used to simulate pulmonary arterial hypertension in vitro. Microarray assay was adopted to screen the dysregulated expressed lncRNAs in HPASMCs to find out the target gene of our study. And RT-qPCR was performed to detect the expression of lncRNA UCA1 under hypoxia and normoxia. After transfection, the relationship between UCA1 and cell proliferation in HPASMCs under hypoxia were determined by cell proliferation assay and relative expression of PCNA. Next, ELISA assays were conducted to measure the protein levels of PCNA and ING5. What’s more, flow cytometry was employed to measure the apoptosis rate in differentially UCA1-expressed HPASMCs. RIP assays were conducted to further clarify the endogenous relationship between UCA1 and ING5 in hypoxic HPASMCs. Finally, the effects of ING5 to HPASMCs were detected after transfection of ING5 and UCA1 to figure out the role of ING5 in HPASMCs. Hypoxia was revealed to induce proliferation and inhibited apoptosis in HPASMCs. Besides, UCA1 was confirmed to be highly expressed under hypoxia compared with normoxia. UCA1 boosted cell proliferation under hypoxia in HPASMCs. However, the apoptosis was suppressed in the hypoxic HPASMCs transfected with pcDNA3.1-UCA1. Further, mechanism studies found that UCA1 competed with ING5 for hnRNP I, so that upregulating UCA1 inhibited the protein levels of ING5. And finally we found that ING5 restrained cell viability, but promoted cell apoptosis in hypoxic HPASMCs, which was reversed by UCA1 over-expression. In summary, our findings manifested that UCA1 promoted proliferation and restrained apoptosis by competing with ING5 for hnRNP I in HPASMCs induced by hypoxia, indicating their potential roles for the cure of hypoxic pulmonary hypertension.

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References

  1. Barry G, Briggs JA, Vanichkina DP, Poth EM, Beveridge NJ, Ratnu VS, Nayler SP, Nones K, Hu J, Bredy TW, Nakagawa S, Rigo F, Taft RJ, Cairns MJ, Blackshaw S, Wolvetang EJ, Mattick JS (2014) The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Mol Psychiatry 19:486–494. https://doi.org/10.1038/mp.2013.45

    Article  CAS  PubMed  Google Scholar 

  2. Batista PJ, Chang HY (2013) Long noncoding RNAs: cellular address codes in development and disease. Cell 152:1298–1307. https://doi.org/10.1016/j.cell.2013.02.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Brock M, Schuoler C, Leuenberger C, Buhlmann C, Haider TJ, Vogel J, Ulrich S, Gassmann M, Kohler M, Huber LC (2017) Analysis of hypoxia-induced noncoding RNAs reveals metastasis-associated lung adenocarcinoma transcript 1 as an important regulator of vascular smooth muscle cell proliferation. Exp Biol Med (Maywood) 242:487–496. https://doi.org/10.1177/1535370216685434

    Article  CAS  Google Scholar 

  4. Campos EI, Chin MY, Kuo WH, Li G (2004) Biological functions of the ING family tumor suppressors. Cell Mol Life Sci 61:2597–2613. https://doi.org/10.1007/s00018-004-4199-4

    Article  CAS  PubMed  Google Scholar 

  5. Farber HW, Loscalzo J (2004) Pulmonary arterial hypertension. N Engl J Med 351:1655–1665. https://doi.org/10.1056/NEJMra035488

    Article  CAS  PubMed  Google Scholar 

  6. Gou WF, Shen DF, Yang XF, Zhao S, Liu YP, Sun HZ, Su RJ, Luo JS, Zheng HC (2015) ING5 suppresses proliferation, apoptosis, migration and invasion, and induces autophagy and differentiation of gastric cancer cells: a good marker for carcinogenesis and subsequent progression. Oncotarget 6:19552–19579. https://doi.org/10.18632/oncotarget.3735

    Article  PubMed  PubMed Central  Google Scholar 

  7. Greco S, Gorospe M, Martelli F (2015) Noncoding RNA in age-related cardiovascular diseases. J Mol Cell Cardiol 83:142–155. https://doi.org/10.1016/j.yjmcc.2015.01.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, Young G, Lucas AB, Ach R, Bruhn L, Yang X, Amit I, Meissner A, Regev A, Rinn JL, Root DE, Lander ES (2011) lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477:295–300. https://doi.org/10.1038/nature10398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Harries LW (2012) Long non-coding RNAs and human disease. Biochem Soc Trans 40:902–906. https://doi.org/10.1042/BST20120020

    Article  CAS  PubMed  Google Scholar 

  10. Huang J, Zhou N, Watabe K, Lu Z, Wu F, Xu M, Mo YY (2014) Long non-coding RNA UCA1 promotes breast tumor growth by suppression of p27 (Kip1). Cell Death Dis 5:e1008. https://doi.org/10.1038/cddis.2013.541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Humbert M, Sitbon O, Simonneau G (2004) Treatment of pulmonary arterial hypertension. N Engl J Med 351:1425–1436. https://doi.org/10.1056/NEJMra040291

    Article  CAS  PubMed  Google Scholar 

  12. Kataoka M, Wang DZ (2014) Non-coding RNAs including miRNAs and lncRNAs in cardiovascular biology and disease. Cells 3:883–898. https://doi.org/10.3390/cells3030883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Khaitan D, Dinger ME, Mazar J, Crawford J, Smith MA, Mattick JS, Perera RJ (2011) The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion. Cancer Res 71:3852–3862. https://doi.org/10.1158/0008-5472.CAN-10-4460

    Article  CAS  PubMed  Google Scholar 

  14. Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, Ding H, Butty VL, Torrey L, Haas S, Abo R, Tabebordbar M, Lee RT, Burge CB, Boyer LA (2013) Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell 152:570–583. https://doi.org/10.1016/j.cell.2013.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu Y, Sun Z, Zhu J, Xiao B, Dong J, Li X (2018) LncRNA-TCONS_00034812 in cell proliferation and apoptosis of pulmonary artery smooth muscle cells and its mechanism. J Cell Physiol 233:4801–4814. https://doi.org/10.1002/jcp.26279

    Article  CAS  PubMed  Google Scholar 

  16. McLaughlin VV, Davis M, Cornwell W (2011) Pulmonary arterial hypertension. Curr Probl Cardiol 36:461–517. https://doi.org/10.1016/j.cpcardiol.2011.08.002

    Article  PubMed  Google Scholar 

  17. Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 10:155–159. https://doi.org/10.1038/nrg2521

    Article  CAS  PubMed  Google Scholar 

  18. Russell M, Berardi P, Gong W, Riabowol K (2006) Grow-ING, age-ING and die-ING: ING proteins link cancer, senescence and apoptosis. Exp Cell Res 312:951–961. https://doi.org/10.1016/j.yexcr.2006.01.020

    Article  CAS  PubMed  Google Scholar 

  19. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F (2011) Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol 8:443–455. https://doi.org/10.1038/nrcardio.2011.87

    Article  CAS  PubMed  Google Scholar 

  20. Semenza GL (2011) Oxygen sensing, homeostasis, and disease. N Engl J Med 365:537–547. https://doi.org/10.1056/NEJMra1011165

    Article  CAS  PubMed  Google Scholar 

  21. Soliman MA, Riabowol K (2007) After a decade of study-ING, a PHD for a versatile family of proteins. Trends Biochem Sci 32:509–519. https://doi.org/10.1016/j.tibs.2007.08.006

    Article  CAS  PubMed  Google Scholar 

  22. Tian Y, Hu Y, Wang Z, Chen K, Zhang L, Wang L, Ren M, Huang A, Tang H (2011) Hepatitis B virus regulates Raf1 expression in HepG2.2.15 cells by enhancing its promoter activity. Arch Virol 156:869–874. https://doi.org/10.1007/s00705-010-0901-z

    Article  CAS  PubMed  Google Scholar 

  23. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett CF, Sharma A, Bubulya PA, Blencowe BJ, Prasanth SG, Prasanth KV (2010) The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39:925–938. https://doi.org/10.1016/j.molcel.2010.08.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ullah M, Pelletier N, Xiao L, Zhao SP, Wang K, Degerny C, Tahmasebi S, Cayrou C, Doyon Y, Goh SL, Champagne N, Cote J, Yang XJ (2008) Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes. Mol Cell Biol 28:6828–6843. https://doi.org/10.1128/MCB.01297-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang F, Li X, Xie X, Zhao L, Chen W (2008) UCA1, a non-protein-coding RNA up-regulated in bladder carcinoma and embryo, influencing cell growth and promoting invasion. FEBS Lett 582:1919–1927. https://doi.org/10.1016/j.febslet.2008.05.012

    Article  CAS  PubMed  Google Scholar 

  26. Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA, Wysocka J, Lei M, Dekker J, Helms JA, Chang HY (2011) A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472:120–124. https://doi.org/10.1038/nature09819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang K, Liu F, Zhou LY, Long B, Yuan SM, Wang Y, Liu CY, Sun T, Zhang XJ, Li PF (2014) The long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489. Circ Res 114:1377–1388. https://doi.org/10.1161/CIRCRESAHA.114.302476

    Article  CAS  Google Scholar 

  28. Wu G, Cai J, Han Y, Chen J, Huang ZP, Chen C, Cai Y, Huang H, Yang Y, Liu Y, Xu Z, He D, Zhang X, Hu X, Pinello L, Zhong D, He F, Yuan GC, Wang DZ, Zeng C (2014) LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity. Circulation 130:1452–1465. https://doi.org/10.1161/CIRCULATIONAHA.114.011675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Xing YN, Yang X, Xu XY, Zheng Y, Xu HM, Takano Y, Zheng HC (2011) The altered expression of ING5 protein is involved in gastric carcinogenesis and subsequent progression. Hum Pathol 42:25–35. https://doi.org/10.1016/j.humpath.2010.05.024

    Article  CAS  PubMed  Google Scholar 

  30. Xue M, Li X, Li Z, Chen W (2014) Urothelial carcinoma associated 1 is a hypoxia-inducible factor-1alpha-targeted long noncoding RNA that enhances hypoxic bladder cancer cell proliferation, migration, and invasion. Tumour Biol 35:6901–6912. https://doi.org/10.1007/s13277-014-1925-x

    Article  CAS  PubMed  Google Scholar 

  31. Yang Y, Chen K, Zhou Y, Hu Z, Chen S, Huang Y (2018) Application of serum microRNA-9-5p, 21-5p, and 223-3p combined with tumor markers in the diagnosis of non-small-cell lung cancer in Yunnan in southwestern China. Onco Targets Ther 11:587–597. https://doi.org/10.2147/OTT.S152957

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zhang E, Han L, Yin D, He X, Hong L, Si X, Qiu M, Xu T, De W, Xu L, Shu Y, Chen J (2017) H3K27 acetylation activated-long non-coding RNA CCAT1 affects cell proliferation and migration by regulating SPRY4 and HOXB13 expression in esophageal squamous cell carcinoma. Nucleic Acids Res 45:3086–3101. https://doi.org/10.1093/nar/gkw1247

    Article  CAS  PubMed  Google Scholar 

  33. Zhang Y, Liu Y, Xu X (2018) Knockdown of LncRNA-UCA1 suppresses chemoresistance of pediatric AML by inhibiting glycolysis through the microRNA-125a/hexokinase 2 pathway. J Cell Biochem 119:6296–6308. https://doi.org/10.1002/jcb.26899

    Article  CAS  PubMed  Google Scholar 

  34. Zheng Y, Song D, Xiao K, Yang C, Ding Y, Deng W, Tong S (2016) LncRNA GAS5 contributes to lymphatic metastasis in colorectal cancer. Oncotarget 7:83727–83734. https://doi.org/10.18632/oncotarget.13384

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zhu B, Gong Y, Yan G, Wang D, Qiao Y, Wang Q, Liu B, Hou J, Li R, Tang C (2018) Down-regulation of lncRNA MEG3 promotes hypoxia-induced human pulmonary artery smooth muscle cell proliferation and migration via repressing PTEN by sponging miR-21. Biochem Biophys Res Commun 495:2125–2132. https://doi.org/10.1016/j.bbrc.2017.11.185

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (81800051, 81570723, 81673423, U1704168), Natural Science Foundation of Henan Province (162300410216, 182300410332, 20171410118), and Research project of Xinxiang Medical University (XYBSKYZZ201626, 2016PN-KFKT-02, 2017BSQDJF). This work was also supported by vascular remodeling intervention and molecular targeted therapy drug development innovation team and cardiovascular remodeling intervention and molecular targeting drug research and development key laboratory.

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Authors and Affiliations

  1. College of Pharmacy, Xinxiang Medical University, No. 601 Jinsui Avenue, Hongqi District, Xinxiang, 453003, Henan, China

    Tian-Tian Zhu, Jin-Ping Quan, Ping Song, Jian Xu, Ming-Xiang Zhang & Peng Li

  2. Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine in Henan Province, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China

    Rui-Li Sun

  3. School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, Henan, China

    Ya-Ling Yin

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  1. Tian-Tian Zhu
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Zhu, TT., Sun, RL., Yin, YL. et al. Long noncoding RNA UCA1 promotes the proliferation of hypoxic human pulmonary artery smooth muscle cells. Pflugers Arch - Eur J Physiol 471, 347–355 (2019). https://doi.org/10.1007/s00424-018-2219-8

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