4. RESULTADOS 1 COORTE
5.4. HSA-MIR-4677-5P
As análises de expressão diferencial das comparações EGA x ELA e EGS x ELA identificaram o hsa-miR-4677-5p como superexpresso em pacientes com estenose carotídea grave. Apesar deste miRNA estar descrito na plataforma miRbase, na literatura ainda não existem artigos sobre sua função e expressão. Para melhor compreender a possível relação do hsa-miR-4677-5p com a estenose carotídea, uma análise de predição de genes alvos foi realizada utilizando as plataformas TargetScan (88) e mirDB (89). A tabela 19 lista três genes que podem ser alvo do hsa-miR-4677-5p e que estão relacionados à aterosclerose.
Tabela 19: Lista de três possíveis genes alvo do hsa-mir-4677-5p que possuem relação com a aterosclerose.
Símbolo do Gene Descrição do Gene
NIN ninein (GSK3B interacting protein)
FGF7 fibroblast growth factor 7
MBNL1 muscleblind like splicing regulator 1
A molécula NIN é uma fosfoproteína que auxilia o ancoramento dos microtúbulos no centrossomo (126). Durante a angiogênese, esta proteína está expressa no citoplasma de células endoteliais, estando relacionada à migração e organização celular (126). Considerando a importância das células endoteliais na formação (40), progressão (86) e desestabilização da
placa aterosclerótica (86), presume-se que o hsa-mir-4677-5p está relacionado à estenose carotídea através da sua interação com a proteína NIN.
Outro possível alvo do hsa-mir-4677-5p é a proteína FGF7, pertencente a família de fatores de crescimento de fibroblastos FGF (127). Esta proteína é expressa em SMC e pode estar relacionada ao desenvolvimento de células vasculares (127). Além disso, o FGF7 também é expresso em artérias humanas, podendo estimular a proliferação de células epiteliais (128). Estes resultados indicam que a proteína FGF7, e consequentemente o hsa-mir-4677-5p, podem estar relacionados à aterosclerose através da atuação nas células vasculares.
O hsa-mir-4677-5p também tem como um possível alvo a MBLN1. Esta proteína regula o splicing alternativo durante a diferenciação de monócitos em macrófagos (129). Nas etapas iniciais da lesão aterosclerótica, a transição de monócitos em macrófagos marca o início do processo inflamatório na parede arterial (42), portanto, é possível que a proteína MBLN1 atue na aterosclerose. Woo et. al. (2020) comprovou esta atuação ao investigar a função do miR- 30b-5p na estenose coronariana (130). No entanto, este estudo demonstrou que, na aterosclerose, a MBLN1 está relacionada à diferenciação de SMC vasculares (130). Desta forma, nossa hipótese é que o hsa-mir-4677-5p pode regular a diferenciação de macrófagos e SMC na estenose carotídea através da sua interação com a proteína MBLN1.
Em conclusão, o hsa-mir-4677-5p está potencialmente relacionado a processos que levam a progressão e desestabilização da placa aterosclerótica. Futuros estudos são necessários para comprovar a sua interação com as proteínas NIN, FGF7 e MBLN1, como também sua atuação na aterosclerose.
6. CONCLUSÃO
Os MicroRNAs miR-508-3p, miR-4677-3p e miR-4677-5p são potenciais candidatos a biomarcadores para a presença da placa aterosclerótica na artéria carótida interna. Além disso, considerando a relevância das vias celulares reguladas por estes miRNAs, como o processo EMT e a internalização de oxLDL, estes resultados indicam que os mir-508-3p, mir-4677-3p, e mir-4677-5p também poderiam ser potenciais alvos de intervenções terapêuticas para o tratamento clínico da aterosclerose.
7. REFERÊNCIAS
1. WHO | The Atlas of Heart Disease and Stroke. WHO. 2010;
2. DATASUS – Ministério da Saúde [Internet]. [cited 2020 Mar 9]. Available from: https://datasus.saude.gov.br/
3. Lotufo PA. Stroke in Brazil: A neglected disease. Sao Paulo Med J. 2005;123(1):3–4. 4. Rosa TE da C, Bersusa AAS, Mondini L, Saldiva SRDM, Nascimento PR, Venancio
SI. Integralidade da atenção às doenças cardiovasculares e diabetes mellitus: o papel da regionalização do Sistema Único de Saúde no estado de São Paulo. Rev Bras Epidemiol. 2009 Jun;12(2):158–71.
5. Abramczuk B, Villela E. A luta contra o AVC no Brasil. ComCiência. 2009;(109):0–0. 6. Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, et al. An updated definition of stroke for the 21st century: A statement for healthcare professionals from the American heart association/American stroke association. Stroke. 2013;44(7):2064–89.
7. Bonita R. Epidemiology of stroke. Lancet. 1992 Feb 8;339(8789):342–4.
8. Cabral, N. L., Longo, A. L., Moro, C. H., Amaral, C. H., & Kiss, H. C. (1997). Epidemiologia dos acidentes cerebrovasculares em Joinville, Brasil: estudo institucional. Arquivos de neuro-psiquiatria, 55(3A), 357-363.
9. De Carvalho JJF, Alves MB, Viana GÁA, Machado CB, Dos Santos BFC, Kanamura AH, et al. Stroke epidemiology, patterns of management, and outcomes in Fortaleza, Brazil: A hospital- based multicenter prospective study. Stroke [Internet]. 2011 Dec [cited 2020 Aug 6];42(12):3341–6.
10. Chamberlain AM. Heart Disease and Stroke Statistics — 2019 Update A Report From the American Heart Association. 2019.
11. Fagan SC, Hess DC, Hohnadel EJ, Pollock DM, Ergul A. Targets for vascular protection after acute ischemic stroke. Stroke. 2004;35(9):2220–5.
12. Dobkin BH, Carmichael ST. The Specific Requirements of Neural Repair Trials for Stroke. Neurorehabil Neural Repair. 2016;30(5):470–8.
13. Boese AC, Le QSE, Pham D, Hamblin MH, Lee JP. Neural stem cell therapy for subacute and chronic ischemic stroke. Stem Cell Res Ther. 2018;9(1):1–17.
14. Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, et al. Definition and Evaluation of Transient Ischemic Attack. Stroke [Internet]. 2009
Jun;40(6):2276–93. Available from: https://www.ahajournals.org/doi/10.1161/STROKEAHA.108.192218
15. Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, et al. Guidelines for the primary prevention of stroke: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke. 2011 Feb;42(2):517–84.
16. Vigitel Brasil 2018: vigilância de fatores de risco e proteção para doenças crônicas por inquérito telefônico : estimativas sobre frequência e distribuição sociodemográfica de fatores de risco e proteção para doenças crônicas nas capitais dos 26 estados brasileiros e no Distrito Federal em 2018 / Ministério da Saúde, Secretaria de Vigilância em Saúde, Departamento de Vigilância de Doenças e Agravos não Transmissíveis e Promoção da Saúde. – Brasília: Ministério da Saúde, 2020.
17. Garcez MR, Pereira JL, de Mello Fontanelli M, Marchioni DML, Fisberg RM. Prevalence of dyslipidemia according to the nutritional status in a representative sample of São Paulo. Arq Bras Cardiol. 2014;103(6):476–84.
18. Da Conceição Ferreira CC, Do Rosário Gondim Peixoto M, Barbosa MA, Silveira ÉA. Prevalência de fatores de risco cardiovascular em idosos usuários do sistema único de saúde de Goiânia. Arq Bras Cardiol. 2010 Oct;95(5):621–8.
19. Adams Jr, H. P., Bendixen, B. H., Kappelle, L. J., Biller, J., Love, B. B., Gordon, D. L., & Marsh 3rd, E. E. (1993). Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. stroke, 24(1), 35-41.
20. Saber H, Thrift AG, Kapral MK, Shoamanesh A, Amiri A, Farzadfard MT, et al. Incidence, recurrence, and long-term survival of ischemic stroke subtypes: A population-based study in the Middle East. Int J Stroke [Internet]. 2017 Oct 1 [cited
2020 Apr 10];12(8):835–43. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/28043215
21. Krishnamurthi R V., Barker-Collo S, Parag V, Parmar P, Witt E, Jones A, et al. Stroke incidence by major pathological type and ischemic subtypes in the Auckland regional community stroke studies: Changes between 2002 and 2011 [Internet]. Vol. 49, Stroke. Lippincott Williams and Wilkins; 2018 [cited 2020 Apr 10]. p. 3–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29212738
22. Braca JA, Bookland MJ, Heiferman DM, Loftus CM. Indications for Carotid Endarterectomy in Patients with Asymptomatic and Symptomatic Carotid Stenosis. In:
Stroke [Internet]. Sixth Edit. Elsevier; 2016. p. 1181–91. Available from: http://dx.doi.org/10.1016/B978-0-323-29544-4.00074-8
23. McColl BW, Allan SM, Rothwell NJ. Systemic infection, inflammation and acute ischemic stroke. Neuroscience [Internet]. 2009;158(3):1049–61. Available from: http://dx.doi.org/10.1016/j.neuroscience.2008.08.019
24. Yazdani SK, Vorpahl M, Ladich E. Pathology and Vulnerability of Atherosclerotic Plaque : Identification , Treatment Options , and Individual Patient Differences for Prevention of Stroke. 2010;297–314.
25. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114(12):1852–66.
26. Sierra C, Coca A, Schiffrin EL. Vascular mechanisms in the pathogenesis of stroke. Curr Hypertens Rep. 2011;13(3):200–7.
27. Mughal MM, Khan MK, Demarco JK, Majid A, Shamoun F, Abela GS. Symptomatic and asymptomatic carotid artery plaque. Expert Rev Cardiovasc Ther. 2011;9(10):1315–30.
28. North American Symptomatic Carotid Endarterectomy Trial Collaborators*. (1991). Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. New England Journal of Medicine, 325(7), 445-453.
29. North American Symptomatic Carotid Endarterectomy Trial Collaborators*. (1991). Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. New England Journal of Medicine, 325(7), 445-453.
30. Grant EG, Benson CB, Moneta GL, Alexandrov A V., Baker JD, Bluth EI, et al. Carotid artery stenosis: grayscale and Doppler ultrasound diagnosis--Society of Radiologists in Ultrasound consensus conference. Ultrasound Q. 2003;19(4):190–8.
31. Scoutt LM, Gunabushanam G. Carotid Ultrasound. Vol. 57, Radiologic Clinics of North America. W.B. Saunders; 2019. p. 501–18.
32. Mortimer R, Machiappan S, Howlett DC. Carotid artery stenosis screening: Where are we now? Vol. 91, British Journal of Radiology. British Institute of Radiology; 2018. 33. Lusis AJ. Atherosclerosis. Nature [Internet]. 2000 Sep;407(6801):233–41. Available
from:http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2826222&tool=pmce ntrez&rendertype=abstract
34. Falk E. Pathogenesis of Atherosclerosis. J Am Coll Cardiol [Internet]. 2006
Apr;47(8):C7–12. Available from:
35. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol [Internet]. 2011 Mar 15;12(3):204–12. Available from: http://www.nature.com/articles/ni.2001
36. Packard RRS, Libby P. Inflammation in atherosclerosis: From vascular biology to biomarker discovery and risk prediction. Clin Chem. 2008;54(1):24–38.
37. Hansson GK, Libby P. The immune response in atherosclerosis: A double-edged sword. Nat Rev Immunol. 2006;6(7):508–19.
38. Martinez-Quinones P, McCarthy CG, Watts SW, Klee NS, Komic A, Calmasini FB, et al. Hypertension Induced Morphological and Physiological Changes in Cells of the Arterial Wall. Am J Hypertens. 2018;31(10):1067.
39. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23 SUPPL.).
40. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473(7347):317–25.
41. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: A marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23(2):168–75.
42. Cai H, Harrison DG. Endothelial Dysfunction in Cardiovascular Diseases: The Role of Oxidant Stress. Circ Res [Internet]. 2000 Nov 10;87(10):840–4. Available from: https://www.ahajournals.org/doi/10.1161/01.RES.87.10.840
43. Packard RRS, Libby P. Inflammation in atherosclerosis: From vascular biology to biomarker discovery and risk prediction. Clin Chem. 2008;54(1):24–38.
44. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(9):2045–51.
45. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the Vulnerable Plaque. J Am Coll Cardiol. 2006;47(8 SUPPL.):0–5.
46. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell [Internet]. 2011;145(3):341–55. Available from: http://dx.doi.org/10.1016/j.cell.2011.04.005 47. Weber C, Noels H. Atherosclerosis: Current pathogenesis and therapeutic options. Nat
Med. 2011;17(11):1410–22.
48. Sayed ASM, Xia K, Salma U, Yang T, Peng J. Diagnosis, prognosis and therapeutic role of circulating miRNAs in cardiovascular diseases. Hear Lung Circ [Internet]. 2014;23(6):503–10. Available from: http://dx.doi.org/10.1016/j.hlc.2014.01.001 49. He L, Hannon GJ. MicroRNAs: Small RNAs with a big role in gene regulation. Nat Rev
50. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11(9):597–610.
51. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6(11):857–66.
52. Ha M, Kim VN. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 2014;15(8):509–24.
53. Carthew RW, Sontheimer EJ. Origins and Mechanisms of miRNAs and siRNAs. Cell
[Internet]. 2009;136(4):642–55. Available from:
http://dx.doi.org/10.1016/j.cell.2009.01.035
54. Griffiths-Jones S. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res [Internet]. 2006 Jan 1;34(90001):D140–4. Available from: https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkj112
55. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861–74. 56. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis,
function and decay. Nat Rev Genet. 2010;11(9):597–610.
57. Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nat Rev Genet. 2008;9(2):102–14. 58. Etheridge A, Lee I, Hood L, Galas D, Wang K. Extracellular microRNA: A new source of biomarkers. Mutat Res - Fundam Mol Mech Mutagen [Internet]. 2011;717(1–2):85– 90. Available from: http://dx.doi.org/10.1016/j.mrfmmm.2011.03.004
59. Kozomara A, Birgaoanu M, Griffiths-Jones S. MiRBase: From microRNA sequences to function. Nucleic Acids Res. 2019;47(D1):D155–62.
60. Zen K, Zhang C-Y. Circulating MicroRNAs: a novel class of biomarkers to diagnose and monitor human cancers. Med Res Rev [Internet]. 2012 Mar;32(2):326–48. Available from: http://doi.wiley.com/10.1002/med.20215
61. Das S, Halushka MK. Extracellular vesicle microRNA transfer in cardiovascular disease. Cardiovasc Pathol [Internet]. 2015;24(4):199–206. Available from: http://dx.doi.org/10.1016/j.carpath.2015.04.007
62. Maffioletti E, Tardito D, Gennarelli M, Bocchio-Chiavetto L. Micro spies from the brain to the periphery: New clues from studies on microRNAs in neuropsychiatric disorders. Front Cell Neurosci. 2014;8(MAR):1–16.
63. Hulsmans M, Holvoet P. MicroRNA-containing microvesicles regulating inflammation in association with atherosclerotic disease. Cardiovasc Res. 2013;100(1):7–18.
64. Pritchard CC, Cheng HH, Tewari M. MicroRNA profiling: Approaches and considerations. Nat Rev Genet. 2012;13(5):358–69.
65. Loyer X, Vion AC, Tedgui A, Boulanger CM. Microvesicles as cell-cell messengers in cardiovascular diseases. Circ Res. 2014;114(2):345–53.
66. Pereira-da-Silva T, Coutinho Cruz M, Carrusca C, Cruz Ferreira R, Napoleão P, Mota Carmo M. Circulating microRNA profiles in different arterial territories of stable atherosclerotic disease: a systematic review. Am J Cardiovasc Dis [Internet].
2018;8(1):1–13. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/29531852%0Ahttp://www.pubmedcentral.nih.g ov/articlerender.fcgi?artid=PMC5840275
67. Malik R, Mushtaque RS, Siddiqui UA, Younus A, Aziz MA, Humayun C, et al. Association Between Coronary Artery Disease and MicroRNA: Literature Review and Clinical Perspective. Cureus. 2017;9(4).
68. Sayed ASM, Xia K, Salma U, Yang T, Peng J. Diagnosis, prognosis and therapeutic role of circulating miRNAs in cardiovascular diseases. Hear Lung Circ [Internet]. 2014;23(6):503–10. Available from: http://dx.doi.org/10.1016/j.hlc.2014.01.001 69. Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM, Andresen D, et al. Refining
clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The Euro Heart Survey on atrial fibrillation. Chest. 2010 Feb 1;137(2):263–72.
70. Burke AP, Kolodgie FD, Farb A, Weber DK, Malcom GT, Smialek J, et al. Healed plaque ruptures and sudden coronary death: Evidence that subclinical rupture has a role in plaque progression. Circulation. 2001;103(7):934–40.
71. Bentzon JF, Sondergaard CS, Kassem M, Falk E. Smooth muscle cells healing atherosclerotic plaque disruptions are of local, not blood, origin in apolipoprotein E knockout mice. Circulation. 2007;116(18):2053–61.
72. Dewdney B, Trollope A, Moxon J, Manapurathe DT, Biros E, Golledge J. Circulating MicroRNAs as Biomarkers for Acute Ischemic Stroke : A Systematic Review PhD ,*. J Stroke Cerebrovasc Dis [Internet]. 2018;27(3):522–30. Available from: https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.09.058
73. Sepramaniam S, Tan J, Tan K, Desilva DA, Tavintharan S, Woon F, et al. Circulating MicroRNAs as Biomarkers of Acute Stroke. 2014;(January):1418–32.
74. Plé H, Landry P, Benham A, Coarfa C, Gunaratne PH, Provost P. The Repertoire and Features of Human Platelet microRNAs. Freson K, editor. PLoS One [Internet]. 2012
Dec 4 [cited 2020 May 5];7(12):e50746. Available from: http://dx.plos.org/10.1371/journal.pone.0050746
75. Zhao L, Wang W, Xu L, Yi T, Zhao X, Wei Y, et al. Integrative network biology analysis identi fi es miR-508-3p as the determinant for the mesenchymal identity and a strong prognostic biomarker of ovarian cancer. Oncogene [Internet]. 2019;2305–19. Available from: http://dx.doi.org/10.1038/s41388-018-0577-5
76. Zang B, Zhao J, Chen C. Lncrna pcat-1 promoted escc progression via regulating anxa10 expression by sponging mir-508-3p. Cancer Manag Res [Internet]. 2019 Dec;11:10841–9. Available from: https://www.dovepress.com/lncrna-pcat-1- promoted-escc-progression-via-regulating-anxa10-expressi-peer-reviewed-article- CMAR
77. Hu P, Zhou G, Zhang X, Song G, Zhan L, Cao Y. Long non-coding RNA Linc00483 accelerated tumorigenesis of cervical cancer by regulating miR-508-3p / RGS17 axis. Life Sci [Internet]. 2019;234(218):116789. Available from: https://doi.org/10.1016/j.lfs.2019.116789
78. Wang Z, Jin J. LncRNA SLCO4A1-AS1 promotes colorectal cancer cell proliferation by enhancing autophagy via miR-508-3p / PARD3 axis. 2019;11(14):4876–89.
79. Guo S, Zeng H, Huang P, Wang S, Xie C, Li S. MiR-508-3p inhibits cell invasion and epithelial-mesenchymal transition by targeting ZEB1 in triple-negative breast cancer. 2018;(March 2013):6379–85.
80. Huang T, Kang W, Zhang B, Wu F, Dong Y, Tong JHM, et al. miR-508-3p concordantly silences NFKB1 and RELA to inactivate canonical NF- κ B signaling in gastric carcinogenesis. Mol Cancer [Internet]. 2016;1–15. Available from: http://dx.doi.org/10.1186/s12943-016-0493-7
81. Li J, Song L, Zhou L, Wu J, Sheng C, Chen H, et al. A MicroRNA signature in gestational diabetes mellitus associated with risk of macrosomia. Cell Physiol Biochem. 2015;37(1):243–52.
82. Kattoor AJ, Goel A, Mehta JL. LOX-1: Regulation, signaling and its role in atherosclerosis. Antioxidants. 2019;8(7):1–15.
83. Jin P, Cong S. LOX-1 and atherosclerotic-related diseases. Clin Chim Acta [Internet]. 2019;491(January):24–9. Available from: https://doi.org/10.1016/j.cca.2019.01.006 84. Kattoor AJ, Pothineni NVK, Palagiri D, Mehta JL. Oxidative Stress in Atherosclerosis.
85. Förstermann U, Xia N, Li H. Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis. Circ Res [Internet]. 2017 Feb 17 [cited 2020 Apr
2];120(4):713–35. Available from:
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.116.309326
86. Pothineni NVK, Karathanasis SK, Ding Z, Arulandu A, Varughese KI, Mehta JL. LOX- 1 in Atherosclerosis and Myocardial Ischemia: Biology, Genetics, and Modulation. J Am Coll Cardiol. 2017;69(22):2759–68.
87. Wesseling M, Sakkers TR, de Jager SCA, Pasterkamp G, Goumans MJ. The morphological and molecular mechanisms of epithelial/endothelial-to-mesenchymal transition and its involvement in atherosclerosis. Vascul Pharmacol [Internet]. 2018;106(February):1–8. Available from: https://doi.org/10.1016/j.vph.2018.02.006 88. Zhang Y, Xu L, Li A, Han X. The roles of ZEB1 in tumorigenic progression and
epigenetic modifications. Biomed Pharmacother [Internet]. 2019;110(September 2018):400–8. Available from: https://doi.org/10.1016/j.biopha.2018.11.112
89. Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife. 2015 Aug 12;4.
90. Wang X. miRDB: A microRNA target prediction and functional annotation database with a wiki interface. RNA. 2008 Jun;14(6):1012–7.
91. Zhang Y, Xu L, Li A, Han X. The roles of ZEB1 in tumorigenic progression and epigenetic modifications. Biomed Pharmacother [Internet]. 2019;110(September 2018):400–8. Available from: https://doi.org/10.1016/j.biopha.2018.11.112
92. Scott CL, Omilusik KD. ZEBs: Novel Players in Immune Cell Development and Function. Trends Immunol [Internet]. 2019;40(5):431–46. Available from: https://doi.org/10.1016/j.it.2019.03.001
93. Zhang P, Sun Y, Ma L. ZEB1: At the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle. 2015;14(4):481–7.
94. Jackson AO, Zhang J, Jiang Z, Yin K. Endothelial-to-mesenchymal transition: A novel therapeutic target for cardiovascular diseases. Trends Cardiovasc Med [Internet]. 2017;27(6):383–93. Available from: http://dx.doi.org/10.1016/j.tcm.2017.03.003 95. Chen PY, Qin L, Baeyens N, Li G, Afolabi T, Budatha M, et al. Endothelial-to-
mesenchymal transition drives atherosclerosis progression. J Clin Invest. 2015 Dec 1;125(12):4514–28.
96. Evrard SM, Lecce L, Michelis KC, Nomura-Kitabayashi A, Pandey G, Purushothaman KR, et al. Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability. Nat Commun. 2016 Jun 24;7(1):1–16.
97. Xiong T, Li J, Chen F, Zhang F. PCAT-1: A novel oncogenic long non-coding RNA in human cancers. Int J Biol Sci. 2019;15(4):847–56.
98. Zhang X, Zhang Y, Mao Y, Ma X. The lncRNA PCAT1 is correlated with poor prognosis and promotes cell proliferation, invasion, migration and EMT in osteosarcoma. Onco Targets Ther. 2018 Jan 31;11:629–38.
99. Sun R, Liu Z, Qiu B, Chen T, Li Z, Zhang X, et al. Annexin10 promotes extrahepatic cholangiocarcinoma metastasis by facilitating EMT via PLA2G4A/PGE2/STAT3 pathway. EBioMedicine [Internet]. 2019;47:142–55. Available from: https://doi.org/10.1016/j.ebiom.2019.08.062
100. Yang Q, Li B, Xu G, Yang S, Wang P, Tang H, et al. Long noncoding RNA LINC00483/microRNA‐144 regulates radiosensitivity and epithelial–mesenchymal transition in lung adenocarcinoma by interacting with HOXA10. J Cell Physiol [Internet]. 2019 Jul 4 ;234(7):11805–21. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/jcp.27886
101. Yang S, Liu T, Sun Y, Liang X. The long noncoding RNA LINC00483 promotes lung adenocarcinoma progression by sponging miR-204-3p. Cell Mol Biol Lett [Internet]. 2019;24(1). Available from: https://doi.org/10.1186/s11658-019-0192-7 102. Nunn C, Mao H, Chidiac P, Albert PR. RGS17/RGSZ2 and the RZ/A family of
regulators of G-protein signaling. Semin Cell Dev Biol. 2006;17(3):390–9.
103. Alexander MR, Murgai M, Moehle CW, Owens GK. Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms. Physiol Genomics. 2012;44(7):417–29.
104. Yu J, Han Z, Sun Z, Wang Y, Zheng M, Song C. LncRNA SLCO4A1-AS1 facilitates growth and metastasis of colorectal cancer through β-catenin-dependent Wnt pathway. J Exp Clin Cancer Res. 2018;37(1):1–12.
105. Tamehiro N, Mujawar Z, Zhou S, Zhuang DZ, Hornemann T, von Eckardstein A, et al. Cell polarity factor Par3 binds SPTLC1 and modulates monocyte serine palmitoyltransferase activity and chemotaxis. J Biol Chem. 2009;284(37):24881–90. 106. Hikita T, Mirzapourshafiyi F, Barbacena P, Riddell M, Pasha A, Li M, et al.
flow. EMBO Rep [Internet]. 2018 Sep 17;19(9). Available from: https://onlinelibrary.wiley.com/doi/abs/10.15252/embr.201745253
107. Jung HY, Fattet L, Tsai JH, Kajimoto T, Chang Q, Newton AC, et al. Apical– basal polarity inhibits epithelial–mesenchymal transition and tumour metastasis by PAR-complex-mediated SNAI1 degradation. Nat Cell Biol [Internet]. 2019 Mar 1 [cited
2020 Apr 5];21(3):359–71. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/30804505
108. Zhou Q, Dai J, Chen T, Dada LA, Zhang X, Zhang W, et al. Downregulation of PKCζ/Pard3/Pard6b is responsible for lung adenocarcinoma cell EMT and invasion. Cell Signal. 2017 Oct 1;38:49–59.
109. Coto E, Reguero JR, Avanzas P, Pascual I, Martín M, Hevia S, et al. Gene variants in the NF-KB pathway (NFKB1, NFKBIA, NFKBIZ) and risk for early-onset coronary artery disease. Immunol Lett [Internet]. 2019;208(January):39–43. Available from: https://doi.org/10.1016/j.imlet.2019.02.007
110. Nair J, Ghatge M, Kakkar V V., Shanker J. Network analysis of inflammatory genes and their transcriptional regulators in coronary artery disease. PLoS One. 2014;9(4).
111. Hoyos-Bachiloglu R, Chou J. Autoimmunity and immunodeficiency [Internet]. Vol. 32, Current Opinion in Rheumatology. Lippincott Williams and Wilkins; 2020
[cited 2020 Apr 6]. p. 168–74. Available from:
http://journals.lww.com/10.1097/BOR.0000000000000688
112. Liang K, Zhu L, Tan J, Shi W, He Q, Yu B. Identifi cation of autophagy signaling network that contributes to stroke in the ischemic rodent brain via gene expression. Neurosci Bull [Internet]. 2015 [cited 2020 Apr 6];31(4):480–90. Available from: http://www.neurosci.cn