The Association between the Expression of MicroRNA-4270 and MicroRNA-4441 with some Metabolic Factors in Iranian Rheumatoid Arthritis Patients
-
Sepideh Ghodoosifar
,
Gholamreza Dehghan
,
Reza Safaralizadeh
,
Behzad Baradaran
,
Mehrzad Hajialiloo
Abstract
MicroRNAs (miRs) play a role in several diseases, such as rheumatoid arthritis (RA). The purpose of this study was to discover new microRNAs and investigate their involvement in RA, examining their connections with inflammation and metabolic markers.
New microRNAs related to RA were predicted using Mirbase and TargetScan databases based on RA target genes. The relationships between miRNAs and targets were visualized with Cytoscape software. Real-time polymerase chain reaction confirmed detectable miRNAs and metabolic factors were assessed using immunoassay and spectrometry methods in RA patients and healthy subjects. Four microRNAs (hsa-miR-153-5p, hsa-miR-4270, hsa-miR-4441, and hsa-miR-6754-5p) showed the highest correlation with RA target genes among millions of microRNAs.
The expression of miR-146b (fold change=1.8) and miR-4441 (fold change=1.7) was notably reduced, while miR-4270 showed upregulation (fold change=1.8) in plasma from RA patients compared to healthy individuals. MiR-6754 exhibited a decrease (fold change=1.3) but was statistically insignificant. MiR-153-5p expression was undetectable in plasma. Receiver operating characteristic (ROC) curve analysis indicated that miR-4441, with an area under the ROC curve (AUC) of 0.7728, and miR-4270 (AUC=0.7353) were promising biomarkers for RA. The expression of these studied miRNAs significantly correlated with essential clinical characteristics, including liver enzymes, cholesterol, phosphorus, and vitamin D3.
Our findings suggest that miR-4270 and miR-4441, present in the circulation, exhibit distinct expression patterns in RA. These microRNAs may serve as links between inflammation and metabolism and represent promising new biomarkers for this disease.
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2. Cornelia M. Weyand & Jörg J. Goronzy. The immunology of rheumatoid arthritis. Nature Immunology. 2021;22:10–18.
3. Bogdan Kolarz, Marek Ciesla, Magdalena Dryglewska, Maria Majdan. Peptidyl Arginine Deiminase Type 4 Gene Promoter Hypo-Methylation in Rheumatoid Arthritis. J Clin Med. 2020;30;9(7):2049.
4. Darrah E, Andrade F. Rheumatoid arthritis and citrullination. Curr Opin Rheumatol. 2018;30(1):72-78.
5. Andonian BJ, Chou C-H, Ilkayeva OR, Koves TR, Connelly MA, Kraus WE, Kraus VB, Huffman KM. Plasma microRNAs in established rheumatoid arthritis relate to adiposity and altered plasma and skeletal muscle cytokine and metabolic profiles. Front Immunol. 2019;10:1475.
6. Lee H-J. Microbe-host communication by small RNAs in extracellular vesicles: vehicles for transkingdom RNA transportation. Int J Mol Sci. 2019;20(6):1487.
7. Bagheri-Hosseinabadi Z, Mirzaei MR, Hajizadeh MR, Asadi F, Rezaeian M, Abbasifard M. Plasma microRNAs (miR-146a, miR-103a, and miR-155) as potential biomarkers for rheumatoid arthritis (RA) and disease activity in Iranian patients. Mediterr J Rheumatol. 2021;32(4):324-330.
8. Lorente-Cebrián S, González-Muniesa P, Milagro FI, Martínez JA. MicroRNAs and other non-coding RNAs in adipose tissue and obesity: emerging roles as biomarkers and therapeutic targets. Clin Sci. 2019;133(1):23-40.
9. Włodarski A, Strycharz J, Wróblewski A, Kasznicki J, Drzewoski J, Sliwinska A. The role of microRNAs in metabolic syndrome-related oxidative stress. Int J Mol Sci. 2020;21(18):6902.
10. Wang Z, Long H, Chang C, Zhao M, Lu Q. Crosstalk between metabolism and epigenetic modifications in autoimmune diseases: a comprehensive overview. Cell Mol Life Sci. 2018;75(18):3353-336.
11. Yousefnia S. A comprehensive review on miR-153: mechanistic and controversial roles of miR-153 in tumorigenicity of cancer cells. Front Oncol. 2022;12:985897.
12. Li X, Ren Y, Zuo T, Long noncoding RNA LINC00978 promotes cell proliferation and invasion in non‑small cell lung cancer by inhibiting miR‑6754‑5p. Mol Med Rep. 2018;18(5):4725-4732.
13. Ciechomska M, Wojtas B, Bonek K, Roszkowski L, Gluszko P, Benes V, Maslinski W. Comprehensive microRNA and transcriptomic profiling of rheumatoid arthritis monocytes: role of microRNA-146b in pro-inflammatory progression. Rheumatology (Oxford). 2021;60(11):5424-5435.
14. Yu H-Y, Meng L-F, Lu X-H, Liu L-H, Ci X, Zhuo Z. Protective effect of miR-146 against kidney injury in diabetic nephropathy rats through mediating the NF-κB signaling pathway. Eur Rev Med Pharmacol Sci. 2021;25(21):6445.
15. Wang Y, Gao W. Effects of TNF-α on autophagy of rheumatoid arthritis fibroblast-like synoviocytes and regulation of the NF-κB signaling pathway. Immunobiol. 2021;226(2):152059.
16. Assadiasl S, Rajabinejad M, Soleimanifar N, Makiyan F, Azizi E, Rezaiemanesh A, et al. MicroRNAs-mediated regulation pathways in rheumatic diseases. Inflammopharmacology. Inflammopharmacology. 2023;31(1):129-144.
17. Rose SA, Wroblewska A, Dhainaut M, Yoshida H, Shaffer JM, Bektesevic A, et al. A microRNA expression and regulatory element activity atlas of the mouse immune system. Nat Immunol. 2021;22(7):914-927.
18. Rezaeepoor M, Pourjafar M, Tahamoli-Roudsari A, Basiri Z, Hajilooi M, Solgi G. Altered expression of microRNAs may predict therapeutic response in rheumatoid arthritis patients. Int Immunopharmacol. 2020;83:106404.
19. Safari F, Damavandi E, Rostamian A-R, Movassaghi S, Imani-Saber Z, Saffari M, et al. Plasma levels of microRNA-146a-5p, microRNA-24-3p, and microRNA-125a-5p as potential diagnostic biomarkers for rheumatoid arthritis. Iran J Allergy Asthma Immunol. 2021;20(3):326-337.
20. Zhou Q, Haupt S, Kreuzer JT, Hammitzsch A, Proft F, Neumann C, et al. Decreased expression of miR-146a and miR-155 contributes to an abnormal Treg phenotype in patients with rheumatoid arthritis. Ann Rheum Dis. 2015;74(6):1265-74.
21. Zheng D, Huo M, Li B, Wang W, Piao H, Wang Y, et al. The role of exosomes and exosomal microRNA in cardiovascular disease. Front Cell Dev Biol. 2021;8:616161.
22. Aminisepehr F, Babaei E, Hosseinpour Feizi MA. Study of the expression of miR-4270 in plasma of patients with breast invasive ductal carcinoma. J Genet Resour. 2018;4(2):85-89.
23. Akrami H, Shamsdin A, Nikmanesh Y, Fattahi MR. Effect of Mir-4270 inhibitor and mimic on viability and stemness in gastric cancer stem-like cells derived from MKN-45 cell line. Iran Biomed J. 2023; 23;27(2 & 3):100-107.
24. Wang H, Huang Zh, Zhao X, Guo B, Ji Zh. MiR-4270 regulates cell proliferation and apoptosis in patients with Sertoli cell-only syndrome by targeting GADD45A and inactivating the NOTCH signaling pathway. Am J Transl Res. 2020;12(9):5730-5740.
25. Pagliari M, Munari F, Toffoletto M, Lonardi S, Chemello F, Codolo G, et al. Helicobacter pylori affects the antigen presentation activity of macrophages modulating the expression of the immune receptor CD300E through miR-4270. Front Immunol. 2017;8:1288.
26. Sun G, Ding X, Bi N, Wang Z, Wu L, Zhou W, et al. Molecular predictors of brain metastasis-related microRNAs in lung adenocarcinoma. PLoS Genet. 2019;15(2):e1007888.
27. Rahman R, Islam T, Zaman T, Shahjaman, Karim R, Huq F, et al. Identification of molecular signatures and pathways to identify novel therapeutic targets in Alzheimer’s disease: insights from a systems biomedicine perspective. Genomics 2020;112(2):1290-1299.
28. Peng X, Wang Q, Li W, Ge G, Peng J, Xu Y, Yang H, Bai J & Geng D. Comprehensive overview of microRNA function in rheumatoid arthritis. Nature bone research 2023; 24;11(1):8.
29. Melayah S, Ghozzi M, Mankaï A, Mechi F, and Ghedira I. Frequency of serological markers of rheumatoid arthritis in patients with IgA anti‐β2 glycoprotein I antibodies. J Clin Lab Anal 2022; 36(7): e24537.
30. GR P, Dihingia P, Kumar Jha A, Gadgade A, and Agarwal D. Rheumatoid Arthritis Co-relation with Anti-CCP Antibodies with special reference to its Prevalence in Asymptomatic First-Degree Relatives. Mediterr J Rheumatol 2022; 33(1): 42–47.
31. Ahmed Elmalt H; Ibrahim A M; Wassef Girgiss M. MicroRNA-146a Expression and Serum Interleukin-17 Level as potential biomarkers for Rheumatoid Arthritis. Egyptian Journal of Chemistry2021;20, 64(7):3423-3429.
32. Aliste-Fernández M, San-José P, Aguadero V. White blood cell count and total protein concentration to predict the absence of microcrystals in synovial fluid. Clin Biochem2020;83:81-85.
33. McAlpine S M, Roberts S E, Hargreaves B K V, Bullock C, Ramsey S, Stringer E, et.al. Differentially Expressed Inflammation-Regulating MicroRNAs in Oligoarticular Juvenile Idiopathic Arthritis. J Rheumatol 2023;50(2):227-235.
34. Zheng F, Yu X, Huang J, Dai Y. Circular RNA expression profiles of peripheral blood mononuclear cells in rheumatoid arthritis patients, based on microarray chip technology. Mol Med Rep 2017;16(6):8029-8036.
35. Giles JT, Sattar N, Gabriel S, Ridker PM, Gay S, Warne C, et al. Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled trial. Arthritis Rheumatol. 2020;72(1):31-40.
36. Lei Q, Yang J, Li L, Zhao N, Lu CH, Lu A, He X. Lipid metabolism and rheumatoid arthritis. Front Immunol 2023; 14: 1190607.
37. T A de Jong , J F Semmelink , S W Denis, M G H van de Sande, R H L Houtkooper, L G M van Baarsen. Altered lipid metabolism in synovial fibroblasts of individuals at risk of developing rheumatoid arthritis. J Autoimmun 2023;134:102974.
38. Jassim HHM, Alnassiri SHM, Mawlood AF, Shnak QA. Relationship of erythrocyte sedimentation rate with the activity of prolidase and liver enzyme in serum of patients with rheumatoid arthritis. Materials Today 2021;43(2):2069-2075.
39. Xia S-F, Qiu Y-Y, Chen L-M, Jiang Y-Y, Huang W, Xie Z-X, et al. Myricetin alleviated hepatic steatosis by acting on microRNA-146b/thyroid hormone receptor b pathway in high-fat diet-fed C57BL/6J mice. Food Funct. 2019;10(3):1465-1477.
40. Jiang K, Li G, Chen W, Song L, Wei T, Li Z, et al. Plasma exosomal miR-146b-5p and miR-222-3p are potential biomarkers for lymph node metastasis in papillary thyroid carcinomas. Onco Targets Ther. 2020;13:1311-1319.
41. Li Q, Wang B, Mu K, Zhang J, Yang Y, Yao W, et al. Increased risk of thyroid dysfunction among patients with rheumatoid arthritis. Front Endocrinol (Lausanne) 2019;9:799.
42. Harrison SR, Li D, Jeffery LE, Raza K, Hewison M. Vitamin D, autoimmune disease and rheumatoid Arthritis. Calcif Tissue Int. 2020;106(1):58-75.
43. Shademanfar S, Bayat N, Rafiee M, Shakibaee A, Arabzadeh E, Ebrahimpour Z. Relationship between serum levels of vitamin D, calcium and phosphorus with disease severity in patients with rheumatoid arthritis referred to a military hospital. J Mar Med. 2022;3(4):229-235.
44. Aslam MM, John P, Bhatti A, Jahangir S, Kamboh MI. Vitamin D as a principal factor in mediating rheumatoid arthritis-derived immune response. Biomed Res Int. 2019;2019:3494937.
2. Cornelia M. Weyand & Jörg J. Goronzy. The immunology of rheumatoid arthritis. Nature Immunology. 2021;22:10–18.
3. Bogdan Kolarz, Marek Ciesla, Magdalena Dryglewska, Maria Majdan. Peptidyl Arginine Deiminase Type 4 Gene Promoter Hypo-Methylation in Rheumatoid Arthritis. J Clin Med. 2020;30;9(7):2049.
4. Darrah E, Andrade F. Rheumatoid arthritis and citrullination. Curr Opin Rheumatol. 2018;30(1):72-78.
5. Andonian BJ, Chou C-H, Ilkayeva OR, Koves TR, Connelly MA, Kraus WE, Kraus VB, Huffman KM. Plasma microRNAs in established rheumatoid arthritis relate to adiposity and altered plasma and skeletal muscle cytokine and metabolic profiles. Front Immunol. 2019;10:1475.
6. Lee H-J. Microbe-host communication by small RNAs in extracellular vesicles: vehicles for transkingdom RNA transportation. Int J Mol Sci. 2019;20(6):1487.
7. Bagheri-Hosseinabadi Z, Mirzaei MR, Hajizadeh MR, Asadi F, Rezaeian M, Abbasifard M. Plasma microRNAs (miR-146a, miR-103a, and miR-155) as potential biomarkers for rheumatoid arthritis (RA) and disease activity in Iranian patients. Mediterr J Rheumatol. 2021;32(4):324-330.
8. Lorente-Cebrián S, González-Muniesa P, Milagro FI, Martínez JA. MicroRNAs and other non-coding RNAs in adipose tissue and obesity: emerging roles as biomarkers and therapeutic targets. Clin Sci. 2019;133(1):23-40.
9. Włodarski A, Strycharz J, Wróblewski A, Kasznicki J, Drzewoski J, Sliwinska A. The role of microRNAs in metabolic syndrome-related oxidative stress. Int J Mol Sci. 2020;21(18):6902.
10. Wang Z, Long H, Chang C, Zhao M, Lu Q. Crosstalk between metabolism and epigenetic modifications in autoimmune diseases: a comprehensive overview. Cell Mol Life Sci. 2018;75(18):3353-336.
11. Yousefnia S. A comprehensive review on miR-153: mechanistic and controversial roles of miR-153 in tumorigenicity of cancer cells. Front Oncol. 2022;12:985897.
12. Li X, Ren Y, Zuo T, Long noncoding RNA LINC00978 promotes cell proliferation and invasion in non‑small cell lung cancer by inhibiting miR‑6754‑5p. Mol Med Rep. 2018;18(5):4725-4732.
13. Ciechomska M, Wojtas B, Bonek K, Roszkowski L, Gluszko P, Benes V, Maslinski W. Comprehensive microRNA and transcriptomic profiling of rheumatoid arthritis monocytes: role of microRNA-146b in pro-inflammatory progression. Rheumatology (Oxford). 2021;60(11):5424-5435.
14. Yu H-Y, Meng L-F, Lu X-H, Liu L-H, Ci X, Zhuo Z. Protective effect of miR-146 against kidney injury in diabetic nephropathy rats through mediating the NF-κB signaling pathway. Eur Rev Med Pharmacol Sci. 2021;25(21):6445.
15. Wang Y, Gao W. Effects of TNF-α on autophagy of rheumatoid arthritis fibroblast-like synoviocytes and regulation of the NF-κB signaling pathway. Immunobiol. 2021;226(2):152059.
16. Assadiasl S, Rajabinejad M, Soleimanifar N, Makiyan F, Azizi E, Rezaiemanesh A, et al. MicroRNAs-mediated regulation pathways in rheumatic diseases. Inflammopharmacology. Inflammopharmacology. 2023;31(1):129-144.
17. Rose SA, Wroblewska A, Dhainaut M, Yoshida H, Shaffer JM, Bektesevic A, et al. A microRNA expression and regulatory element activity atlas of the mouse immune system. Nat Immunol. 2021;22(7):914-927.
18. Rezaeepoor M, Pourjafar M, Tahamoli-Roudsari A, Basiri Z, Hajilooi M, Solgi G. Altered expression of microRNAs may predict therapeutic response in rheumatoid arthritis patients. Int Immunopharmacol. 2020;83:106404.
19. Safari F, Damavandi E, Rostamian A-R, Movassaghi S, Imani-Saber Z, Saffari M, et al. Plasma levels of microRNA-146a-5p, microRNA-24-3p, and microRNA-125a-5p as potential diagnostic biomarkers for rheumatoid arthritis. Iran J Allergy Asthma Immunol. 2021;20(3):326-337.
20. Zhou Q, Haupt S, Kreuzer JT, Hammitzsch A, Proft F, Neumann C, et al. Decreased expression of miR-146a and miR-155 contributes to an abnormal Treg phenotype in patients with rheumatoid arthritis. Ann Rheum Dis. 2015;74(6):1265-74.
21. Zheng D, Huo M, Li B, Wang W, Piao H, Wang Y, et al. The role of exosomes and exosomal microRNA in cardiovascular disease. Front Cell Dev Biol. 2021;8:616161.
22. Aminisepehr F, Babaei E, Hosseinpour Feizi MA. Study of the expression of miR-4270 in plasma of patients with breast invasive ductal carcinoma. J Genet Resour. 2018;4(2):85-89.
23. Akrami H, Shamsdin A, Nikmanesh Y, Fattahi MR. Effect of Mir-4270 inhibitor and mimic on viability and stemness in gastric cancer stem-like cells derived from MKN-45 cell line. Iran Biomed J. 2023; 23;27(2 & 3):100-107.
24. Wang H, Huang Zh, Zhao X, Guo B, Ji Zh. MiR-4270 regulates cell proliferation and apoptosis in patients with Sertoli cell-only syndrome by targeting GADD45A and inactivating the NOTCH signaling pathway. Am J Transl Res. 2020;12(9):5730-5740.
25. Pagliari M, Munari F, Toffoletto M, Lonardi S, Chemello F, Codolo G, et al. Helicobacter pylori affects the antigen presentation activity of macrophages modulating the expression of the immune receptor CD300E through miR-4270. Front Immunol. 2017;8:1288.
26. Sun G, Ding X, Bi N, Wang Z, Wu L, Zhou W, et al. Molecular predictors of brain metastasis-related microRNAs in lung adenocarcinoma. PLoS Genet. 2019;15(2):e1007888.
27. Rahman R, Islam T, Zaman T, Shahjaman, Karim R, Huq F, et al. Identification of molecular signatures and pathways to identify novel therapeutic targets in Alzheimer’s disease: insights from a systems biomedicine perspective. Genomics 2020;112(2):1290-1299.
28. Peng X, Wang Q, Li W, Ge G, Peng J, Xu Y, Yang H, Bai J & Geng D. Comprehensive overview of microRNA function in rheumatoid arthritis. Nature bone research 2023; 24;11(1):8.
29. Melayah S, Ghozzi M, Mankaï A, Mechi F, and Ghedira I. Frequency of serological markers of rheumatoid arthritis in patients with IgA anti‐β2 glycoprotein I antibodies. J Clin Lab Anal 2022; 36(7): e24537.
30. GR P, Dihingia P, Kumar Jha A, Gadgade A, and Agarwal D. Rheumatoid Arthritis Co-relation with Anti-CCP Antibodies with special reference to its Prevalence in Asymptomatic First-Degree Relatives. Mediterr J Rheumatol 2022; 33(1): 42–47.
31. Ahmed Elmalt H; Ibrahim A M; Wassef Girgiss M. MicroRNA-146a Expression and Serum Interleukin-17 Level as potential biomarkers for Rheumatoid Arthritis. Egyptian Journal of Chemistry2021;20, 64(7):3423-3429.
32. Aliste-Fernández M, San-José P, Aguadero V. White blood cell count and total protein concentration to predict the absence of microcrystals in synovial fluid. Clin Biochem2020;83:81-85.
33. McAlpine S M, Roberts S E, Hargreaves B K V, Bullock C, Ramsey S, Stringer E, et.al. Differentially Expressed Inflammation-Regulating MicroRNAs in Oligoarticular Juvenile Idiopathic Arthritis. J Rheumatol 2023;50(2):227-235.
34. Zheng F, Yu X, Huang J, Dai Y. Circular RNA expression profiles of peripheral blood mononuclear cells in rheumatoid arthritis patients, based on microarray chip technology. Mol Med Rep 2017;16(6):8029-8036.
35. Giles JT, Sattar N, Gabriel S, Ridker PM, Gay S, Warne C, et al. Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled trial. Arthritis Rheumatol. 2020;72(1):31-40.
36. Lei Q, Yang J, Li L, Zhao N, Lu CH, Lu A, He X. Lipid metabolism and rheumatoid arthritis. Front Immunol 2023; 14: 1190607.
37. T A de Jong , J F Semmelink , S W Denis, M G H van de Sande, R H L Houtkooper, L G M van Baarsen. Altered lipid metabolism in synovial fibroblasts of individuals at risk of developing rheumatoid arthritis. J Autoimmun 2023;134:102974.
38. Jassim HHM, Alnassiri SHM, Mawlood AF, Shnak QA. Relationship of erythrocyte sedimentation rate with the activity of prolidase and liver enzyme in serum of patients with rheumatoid arthritis. Materials Today 2021;43(2):2069-2075.
39. Xia S-F, Qiu Y-Y, Chen L-M, Jiang Y-Y, Huang W, Xie Z-X, et al. Myricetin alleviated hepatic steatosis by acting on microRNA-146b/thyroid hormone receptor b pathway in high-fat diet-fed C57BL/6J mice. Food Funct. 2019;10(3):1465-1477.
40. Jiang K, Li G, Chen W, Song L, Wei T, Li Z, et al. Plasma exosomal miR-146b-5p and miR-222-3p are potential biomarkers for lymph node metastasis in papillary thyroid carcinomas. Onco Targets Ther. 2020;13:1311-1319.
41. Li Q, Wang B, Mu K, Zhang J, Yang Y, Yao W, et al. Increased risk of thyroid dysfunction among patients with rheumatoid arthritis. Front Endocrinol (Lausanne) 2019;9:799.
42. Harrison SR, Li D, Jeffery LE, Raza K, Hewison M. Vitamin D, autoimmune disease and rheumatoid Arthritis. Calcif Tissue Int. 2020;106(1):58-75.
43. Shademanfar S, Bayat N, Rafiee M, Shakibaee A, Arabzadeh E, Ebrahimpour Z. Relationship between serum levels of vitamin D, calcium and phosphorus with disease severity in patients with rheumatoid arthritis referred to a military hospital. J Mar Med. 2022;3(4):229-235.
44. Aslam MM, John P, Bhatti A, Jahangir S, Kamboh MI. Vitamin D as a principal factor in mediating rheumatoid arthritis-derived immune response. Biomed Res Int. 2019;2019:3494937.
| Files | ||
| Issue | Vol 22 No 6 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v22i6.14643 | |
| Keywords | ||
| Biomarkers Inflammation Metabolomics MicroRNAs Rheumatoid arthritis | ||
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How to Cite
1.
Ghodoosifar S, Dehghan G, Safaralizadeh R, Baradaran B, Hajialiloo M. The Association between the Expression of MicroRNA-4270 and MicroRNA-4441 with some Metabolic Factors in Iranian Rheumatoid Arthritis Patients. Iran J Allergy Asthma Immunol. 2023;22(6):536-550.
